Skip to main content

Advanced Exercise Prescription for Cancer Patients and its Application in Germany

Abstract

The scientific interest of exercise medicine for the treatment of cancer is ever expanding. Recently published and updated guidelines for exercise training in cancer patients by the American College of Sports Medicine (ACSM), the Clinical Oncology Society of Australia (COSA) or the Exercise and Sports Science Australia (ESSA) are leading the way towards an individualized approach for exercise prescription. These guidelines provide physicians and therapists with a comprehensive and detailed overview about the beneficial effects of exercise training and, more so, summarize the evidence on potential dose–response mechanisms, including pathways of exercise-induced stimuli to counteract tumour microenvironmental pathologies. However, the most optimal types and doses of exercise training across the cancer disease and treatment continuum are yet to be determined. Therefore, the purpose of this narrative review was to illustrate the current implications but also limitations of exercise training during the different stages of cancer therapy, as well as to discuss necessary future directions. As a second purpose, special attention will be given to the current role of exercise in the treatment of cancer in Germany.

Introduction

The scientific interest of exercise as medicine continues to grow rapidly. After the American College of Sports Medicine (ACSM) and the American Medical Association (AMA) launched their ground-breaking initiative of “Exercise is Medicine” in 2007 [82], the scientific publications focusing on exercise as medicine listed in PubMed have almost tripled. However, the history of exercise prescription dates back to ancient times and many of the recent developments are actually not novel but much rather are rediscovered after periods of exercise science research with a focus on athletic performance [93].

While initially the term exercise is medicine was understood as a means to improve population health and well-being by raising awareness of health care providers to focus on physical activity as a vital sign, nowadays it is much rather considered as a crucial part for the therapy of numerous chronic diseases [73]. In fact, current studies provide evidence for exercise to complimentarily support primary therapy of more than 26 chronic diseases, such as psychiatric, neurological, metabolic, cardiovascular, pulmonary, musculoskeletal, and oncological diseases [73]. Moreover, in a recent editorial published in the British Medical Journal, exercise medicine was referred to as a “miracle cure”, highlighting current evidence on the beneficial effects of exercise in the prevention and treatment of chronic diseases [37]. However, also miracle cures follow a dose–response relationship and so does the polypill exercise, requiring a tailored prescription.

Considering the wealth of studies primarily focusing on exercise medicine, it is of little surprise that the field of exercise oncology is rapidly expanding as well, with indexed publications having increased by over 400% during the past decade. Interestingly, it was not until 2009 [46] and 2010 [84] when the first physical activity guidelines for cancer survivors were published. Since the evidence was scarce during that time, these guidelines initially followed a rather generic approach, and did not substantially differ from the WHO recommendations for healthy individuals or patients of other chronic diseases (i.e. 150 min of moderate aerobic activity or 75 min of vigorous aerobic activity, as well as two to three resistance exercise sessions per week) [98]. Intensified research efforts especially over the past decade, however, have eventually accumulated in recently published guideline papers by the Clinical Oncology Society of Australia (COSA) [19], Exercise and Sports Science Australia (ESSA) [45] and the ACSM [14, 72, 83], providing a first step towards precision exercise medicine in the treatment of cancer.

However, even though these guidelines provide thorough recommendations for scientists, practitioners and patients alike, the most optimal types and doses of exercise training across the cancer control continuum [20] are yet to be defined. In line with this, there seems to be a heterogeneous acceptance and understanding evolving around the beneficial effects of exercise for different cancer entities, and potential limitations or even harms of exercise in this vulnerable population often receive insufficient attention. Therefore, the aim of this narrative review is to illustrate the current implications and limitations of exercise training during the different stages of cancer therapy as well as to discuss necessary future directions. As a second purpose, special attention will be given to the current role of exercise in the treatment of cancer in Germany.

Implications for Physical Exercise in Cancer

According to the World Health Organization (WHO), cancer is the second leading cause of death globally, with over 9.6 million deaths in 2018 [12]. In fact, it is quite similar in Germany where only cardiovascular diseases cause more annual deaths [48]. However, concomitantly with the steady increase in cancer-related mortality and newly diagnosed malignant tumours, the survival rates are also increasing. On one hand, this dichotomous development can be explained by the change in demographics and, thus, a growing population of elderly as well as a higher incidence of cancer with increasing age [12, 48]. On the other hand, early detection of the disease and treatment options have significantly improved over the past decades, leading to improved survival rates [48]. Earlier cancer detection may also contribute to the increasing number of young adults diagnosed with cancer [61]. This, in turn, may prolong therapy and aftercare but also further increases the need of supportive strategies, such as psycho-oncological [97], nutritional [97] and exercise interventions [51, 73] as well as programs specifically tailored to facilitate return to work [11].

Although cancer is a complex and heterogeneous disease with numerous distinct underlying physiological and pathophysiological mechanisms, some similarities in the tumour genesis are observed across different cancer entities. These cancer hallmarks are summarized as follows: (i) sustaining proliferative signalling; (ii) evading growth suppressors; (iii) resisting cell death (apoptosis); (iv) enabling replicative immortality; (v) inducing angiogenesis; (vi) activating invasion and metastases; (vii) reprogramming of energy metabolism; and (viii) evading immune destruction [42]. Furthermore, systemic inflammation, tissue hypoxia and genome instability are contributing to the heterogeneity of cancer-related deconditioning by fortifying the underlying hallmarks [42]. The pathogenesis of tumour development is reviewed in detail elsewhere [42]. However, it is important to bear in mind that cancer tissue also affects surrounding healthy cells, causing dysfunction such as an altered metabolism, consequently inducing a number of side-effects, such as cachexia as well as immunosuppression, pain and fatigue [42, 71]. Thus, the treatment should target both the disease and the side effects of the disease, as well as the treatment-induced health consequences.

Considering the complexity in cancer genesis and entities as well as the heterogeneous and rapidly changing therapy approaches, treatment side effects, comorbidities and sequelae as well as individual therapy responses [42, 71], it is inevitable to continuously optimize both primary medical treatment as well as supportive therapies [71, 97]. It is well established that physical exercise induces physiological stimuli on molecular, cellular, tissue and systemic levels [56]. Thus, physical exercise may at least theoretically target both the disease itself as well as the disease and treatment-induced side effects [4, 7, 17, 56]. In a previous animal model, it was shown that exercise was actually similarly effective as cyclophosphamide treatment in attenuating tumour growth, while this response was almost doubled when exercise and chemotherapy were combined [8]. Moreover, a comprehensive overview on the acute and chronic regulating effects of exercise on the tumour microenvironment was recently published in Nature Reviews Cancer [56]. The authors summarized that exercise training might have the greatest effects in reprogramming cancer hallmarks by targeting the three key mechanisms of metabolism, angiogenesis and immune response [56]. Thus, the unique therapeutic benefits of exercise training may lie in its local and systemic modulating effects, which may be best controlled by tailored exercise prescriptions.

However, despite possible direct effects on tumour biology, it is indisputable that physical exercise should not be understood as a replacement of primary therapy but much rather may be considered an adjuvant treatment. As such, regular physical exercise is known to affect metabolic, endocrine, gastrointestinal, cardiopulmonary, neurological and immunological pathways, all of which might be affected by both cancerous cells and cancer treatment [4, 7]. Previous studies have shown numerous benefits of exercise training, including improved cardiovascular fitness [53] and muscle strength [91], reduced rates of lymphedema [57] and neuropathies [24], lowered cancer-related fatigue [21], reduced tumour growth [26] or relapse [30] and improved immunological function [51], as well as psychological well-being and quality of life [35].

However, despite the promising results of regular exercise for the adjuvant treatment of cancer, the majority of studies are lacking sufficient quality in reporting and transparency of exercise prescription and guidelines [27], making it difficult to apply their findings to other entities and real-life scenarios. Moreover, a large heterogeneity exists in terms of the timing of exercise interventions in the cancer control continuum (i.e. exercise administered prior to cancer therapy [prehabilitation], during targeted therapy, during rehabilitation and aftercare or during long-term survivorship) [17, 20], as well as in terms of the exercise mode (e.g. low-intensity vs. high-intensity training) and type (e.g. aerobic vs. strength training). The identification of dose–response relationships for specific types of training is likely a key in optimizing exercise prescription for cancer patients. However, research is often limited by ethical dilemmas, especially when certain types of training has been proven extremely beneficial and may no longer be withheld for certain cancer patient populations. Consequently, even well-controlled studies often utilize combined training approaches [63], making it impossible to identify sole contributions of individual training components.

Collectively, these concerns were summarized in a wider context by a recent editorial published in the British Journal of Sports Medicine 2016, where it was questioned whether research in exercise medicine is actually caught in an efficacy trap [6]. This question was reinforced by data on the exercise adherence, which often varies between only 40% and 50% [41]. However, even though this is quite similar to that reported in drug trials [6], it was postulated that there is a general confidence in licensed drugs being effective but this does not appear to be true for exercise training. Although it should be emphasized that this editorial did not specifically focus on exercise oncology, the concerns on missing efficacy are underlined by a current lack of clinical phase IV trials focussing on exercise interventions in oncological patients. Fortunately, some large-scale randomized controlled trials with the primary endpoint of overall survival are open for recruitment at present [67, 68, 70], some of these trials even being international multicentre trials with a supervised exercise period ranging from 6 to 12 months [69, 70]. However, despite overall survival also an in depth understanding of the underlying mechanisms by which exercise training can tackle both the disease and its side effects is fundamental. By that, it is likely that the next decade of research in exercise oncology will make another substantial step towards a precision exercise medicine approach.

Individualized Exercise Prescription for Cancer Patients

To develop concepts of individualized (i.e. tailored) exercise prescription, distinguishing between physical activity and structured exercise training is required. Physical activity is generally defined as skeletal muscle movement that results in elevated energy expenditure above resting levels and includes domains such as walking, hiking or gardening [32]. Exercise training on the other hand, expands on this definition by being a planned, structured and repetitive activity, aiming to improve physical performance. This is why exercise is characterized by specified criteria such as frequency, intensity, time, type, volume, and progression [32]. Considering exercise as medicine, the distinct definition of physical activity and exercise may also be achieved based on the primary goal, where physical activity is aimed at preventing chronic disease and disability. Exercise training, however, is prescribed towards a well-defined target like weight reduction, improved physical fitness, or even more profound the reprogramming of epigenetics or improvement of immune function.

In general, evidence from epidemiological studies suggests that greater volumes of physical activity contribute to a stronger decrease of morbidity induced by various types of chronic diseases [28]. Thus, a personalized approach for exercise prescription will further facilitate health care providers to define more accurately the optimal exercise regimen in the prevention or treatment of particular disease or treatment-induced side effects [75]. In fact, first studies indicating a potential dose–response mechanism in the reduction of cancer treatment-induced side effects are emerging [14]. Consequently, a sufficient and distinct training stimulus is required to induce meaningful physiological adaptations and improved clinical outcomes [4, 17]. Thus, individualizing exercise prescription may help to address possible variabilities in health-related outcomes. Furthermore, this would enable exercise programs to be tailored for the individual phenotype [18], also considering different needs based on the cancer therapy and treatment tolerance.

The need for individualized exercise prescription is highlighted by studies that specifically identify individuals that do not systematically improve exercise capacity, even though the training intervention was well-structured [78]. Ahtiainen and colleagues showed that approximately 7% of healthy individuals do not improve muscle mass following standardized strength training, while this number was increased to approximately 30% when gains in maximal strength are considered [1]. Moreover, extensive variations were observed for muscle hypertrophy (range from 11% to 30%) and maximal strength (− 8% to 60%), irrespective of age and sex [1]. Similar findings were also reported for changes in the aerobic capacity following a 20-week endurance training program, where 7% of the subjects improved maximal oxygen consumption by only 100 mL/min, while another 8% of the individuals improved up to 700–1000 mL/min,thus, indicating a great range of individual responses [10].

In cancer patients, the identification of low- and/or high-responders is often hindered by studies typically reporting the overall treatment effect of the entire study sample rather than individual responses [16, 53, 66, 91]. This may mask heterogeneous training responses and, therefore, might lead to false conclusions on the success of a given training program. This is also underlined by controversial results of studies assessing the effects of physical training performed concomitantly to medical treatment. While some studies have shown physiological and clinically meaningful adaptations [9, 64], in other studies prolonged exercise training did not induce beneficial changes [16, 66, 100].

Within a precision exercise medicine approach, the question arises on ways of avoiding low responders to a given training program. Based on the current literature, there are several aspects that need to be considered. Above all, it is obvious that an in-depth understanding of the mechanisms underlying the cancer genesis and/or treatment response in patient phenotypes is a necessity to tailored treatment strategies [18], including individualized exercise prescription and systematic long-term planning (i.e. training periodization) [75]. This approach is similar to clinical trials in which personalized doses of medical treatment have been successfully determined [99]. Another way to reduce the number of low responders might be to alter the training modalities, such as type, frequency, intensity or volume, concomitantly to the treatment (e.g. strenuous training in treatment-free weeks) [78]. In this context, also perceptual responses need to be considered. For example, high-intensity interval training may require less time compared to moderate-intensity continuous training but the associated shortness of breath, leg pain and fatigue observed during strenuous exercise may be bothersome [94]. It has previously been suggested that exercise at sub-threshold intensities is perceived pleasant for most individuals, while large inter-individual variability is observed when training at the second ventilatory or lactate threshold, and homogenously negative perceptions result from training at maximal intensities [36]. Thus, both physiological aspects but also subjective well-being need to be considered when designing proper exercise prescription in cancer treatment.

Other aspects might be related to both the timing and type of exercise within the cancer control continuum [17, 20, 29]. Exercise during therapy is often directly affected by the primary treatment and may, thus, require constant adjustments [55]. However, numerous studies have provided evidence to commence exercise already well before treatment (i.e. prehabilitation) [15, 20]. For example, Centemero and colleagues showed in prostate cancer patients, that regular pelvic floor muscle exercises prior to radical prostatectomy will lead to a significantly lower incontinence burden post-surgery [15]. These findings would likely have not been achieved if general aerobic training would have been performed, underlining the importance of selecting the right dose of training, similar to drug prescriptions.

Furthermore, exercise interventions for oncological patients may also be improved by incorporating health- and wellness technology. This could have the potential to further improve the understanding of associations between physical activity, health and cancer [85]. Moreover, tracking of physical activity might provide valuable information on coping with primary treatment as well as treatment-related and/or disease-related side effects. However, despite the promising potential of technology-based/technology-supported approaches, its use and acceptance in everyday routines is still limited [79, 85]. Future steps should include a wider use of such technologies to track habitual physical activity but also adherence and compliance of exercise programs. While large trials that might lead in this direction are currently running [44, 77], future studies should also aim to implement the use of wearables to tailor exercise programming, i.e. by providing feedback on recovery needs following both training sessions and/or cancer treatments (e.g. chemotherapy infusion). In fact, we believe especially the latter is a necessity to assure the prescription of most appropriate doses of training for individual patients.

To combine the wealth of aspects that require attention when prescribing individualized exercise regimens to cancer patients, Scott and colleagues suggested an exploratory paradigm, in which tailored exercise prescriptions are based on an initial phenotyping of both clinical and medical profiles, permitting stratification of patients into homogenous subgroups [18, 86]. In their example provided, cancer patients are initially stratified based on the risk of developing cardiotoxicity [86]. Based on an additional cardiopulmonary exercise testing, the exercise prescription is further refined by prescribing exercise based on intensity zones. However, individualized exercise prescription may only be provided based on a multidimensional data approach, requiring advanced analytics for both disease-related risk stratification and exercise prescription. Although this approach is labour-intensive, it may easily be modified based on other contraindications, such as bone metastases, fatigue or polyneuropathies, facilitating exercise prescription throughout the cancer control continuum.

Limitations of Exercise Medicine for Cancer Patients

Physical exercise is generally considered safe and relatively easy to implement throughout all phases of the cancer control continuum [17, 20]. However, the exercise-induced therapeutic potential is specific to the condition of the patient, determined by the disease, the disease status, as well as the primary therapy. Thus, exercise training may come along with contraindications that require careful consideration, similar to the primary therapy such as surgery, radiotherapy or drugs. These may include but are not limited to acute cardiovascular complications, such as unstable angina, severe aortic stenosis or uncontrolled hypertension [76], as well as alterations in hematologic parameters like low number of erythrocytes, platelets or haematocrit [45]. Furthermore, some types of exercise may be contraindicated in certain subpopulations, treatments or in individual diseased states. For example, caution is required for patients undergoing radiotherapy when exercise is performed in the pool, due to an increased risk of burn site irritation [90]. In addition, limitations may also exist for advanced cancer patients who are prone to develop bone metastases. However, while it was previously suggested to avoid heavy exercise load on metastasized areas to reduce the risk for fractures [88], evidence is emerging that strength training seems to be safe and feasible for these patients as well [43, 88].

Despite the type of exercise, certain exercise modalities including exercise intensity need to be considered as they may affect tumour-intrinsic factors, such as metabolism, growth and crosstalk with surrounding tissues [49]. Cancer cells are generally characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions [95, 96], known as the Warburg Hypothesis [74]. According to this, the tumour bypasses regular mitochondrial function by glycolytic conversion of glucose molecules to lactic acid for ATP production [49]. Consequently, it is not surprising that blood lactate seems to play an important role in the tumour microenvironment and may affect tumour biology by its autocrine, paracrine and endocrine properties [13, 49, 58]. Current theories are indicating that cancer cells may switch between production and consumption of blood lactate insinuating a dynamic tumour metabolism [13, 49]. Furthermore, it is also discussed that tumours are consuming blood lactate produced by noncancerous cells, which is called the “reverse Warburg effect” [39]. In fact, these observations led some authors to conclude that increased blood lactate concentrations may contribute to tumour growth and increased rates of recurrence, as was previously shown in a mouse model [38, 39, 58].

In light of these concerns, it is crucial to understand the role of exercise-induced increased blood lactate concentrations to assure that the provided training stimulus does not augment carcinogenic mechanisms. Importantly, exercise-induced blood lactate accumulation following high-intensity exercise may actually impede glycolysis and lactate production in healthy individuals [50], potentially counteracting the carcinogenic microenvironment mechanisms [49]. Consequently, it appears that the systemic acidosis induced by strenuous exercise takes on a crucial role to interfere with the carcinogenic mechanisms potentially affecting tumour growth and/or recurrence [49, 89]. These facts are supported by a 40% decreased risk of overall cancer mortality in elite athletes exposed to long-term strenuous exercise compared to the general population [49, 80]. However, the role of exercise-induced blood lactate and, thus, the role of high-intensity exercise needs further investigations to identify its importance within the cancer control continuum.

To date, the majority of studies have assessed models of exercise prescription as an isolated adjuvant treatment strategy. However, exercise medicine should always be addressed in the context of other medical treatments, i.e. the primary therapy. In a recent review, a theoretical frame work was established, describing how exercise may affect a drug’s absorption, distribution, metabolism, and excretion (i.e. pharmacokinetics) and, thus, potentially influence pharmacodynamics [62]. This is because acute exercise transiently diverts blood away from the liver and reduces the plasma volume, both of which may have profound effects on the blood concentration of a given drug. Moreover, chronic adaptations induced by regular exercise, such as changes in body composition and enhanced enzyme activities, may potentially alter drug pharmacokinetics to a significant extent [62]. While exercise-induced increases in peripheral blood flow have previously been associated with positive effects of drug delivery in cancer patients [4], other metabolic effects of exercise may actually interfere with the drug action, possibly becoming most problematic in cancer patients with comorbidities. It appears that interactions of exercise and drugs are among the most serious concerns for exercise prescription but to date only very few studies have addressed this specifically [62]. Thus, advancing exercise prescription requires also an in-depth analysis of possible interference of the exercise regimen with the primary medical therapy.

Similarly, interactions of exercise and cancer-induced fatigue (CRF) bear a potential for adverse health effects. CRF is among the most common side effects of cancer and cancer treatment, with over 80% of patients being affected during chemo- and/or radiotherapy [47]. The aetiology of CRF is complex and includes direct effects of the cancer and tumour burden as well as treatment side effects and comorbidities, such as thyroid dysfunction, sleep disturbances and psychosocial factors [47]. Currently, there is only very limited evidence about the efficacy for any pharmacological treatments of CRF [65] and evidence points towards beneficial effects of exercise training on CRF [21]. However, a recent meta-analysis summarizing the results of previously published reviews and meta-analysis revealed a quite clear lack of certainty regarding the benefits of exercise in CRF [54]. In fact, while the overall conclusion was that exercise does not seem to increase CRF burden, it was also suggested that the efficacy of exercise depends on the stages of CRF induced by the primary treatment, the patient’s phenotype, as well as the already existing period of symptoms.

Interestingly, a recent randomized controlled trial including patients affected by CRF showed that up to 33% of cancer patients may actually experience an acute worsening of CRF following exercise [94]. This phenomenon is commonly referred to as post-exertional malaise and was initially described as a cardinal symptom in myalgic encephalitis and/or the chronic fatigue syndrome. In CRF patients, post-exercise malaise may last for several hours after the completion of a demanding physical or mental activity [94], possibly affecting long-term adherence to exercise as an adjuvant therapy. Therefore, an individually tailored and multicomponent approach may be advisable, and should include individual activity pacing [94]. Indeed, an often overlooked aspect of exercise prescription is a structured recovery process. In contrast to the vast knowledge on periodization models in elite athletes, also in terms of carefully planned periods with reduced training intensity and/or duration (i.e. tapering), this has to the best of our knowledge not yet been thorougly considered for exercise prescription in cancer patients. However, periods of planned de-load or structured reductions in volume, frequency or intensity might be an effective method to counterbalance cancer- and treatment-induced side effects.

Other limitations of exercise interventions in cancer patients may be induced by the interactions of concurrent exercise and active primary treatment. For example, due to the hormone-dependent tumour growth, advanced prostate cancer patients are commonly treated by androgen deprivation therapy (ADT). However, anabolic steroids such as testosterone are essential to muscle growth [5]. Consequently, significant reductions of circulating testosterone concentrations induced by ADT may induce adverse effects such as a loss of lean mass [31], bone mineral density [31] and muscle strength [2], impacting on independency and overall quality of life. Recent studies have shown that muscle mass is an important predictor of overall survival in patients with various cancer entities [59], and it was previously suggested that regular strength training will ameliorate the treatment-induced declines in muscle mass. However, in a recent meta-analysis, we showed that studies do not support this assumption at present, especially when training is commenced months after the initiation of ADT treatment [16]. These findings clearly highlight the limitations of sole exercise training for some patients and at the same time make a case for multimodal approaches, for example including nutritional interventions.

Even though in this section we have highlighted some considerations for possible detrimental effects of exercise in cancer treatment, studies reporting potential adverse effects are very rare. In a recent systematic review by Segal and colleagues, it appeared that exercise-related adverse events and severe adverse events were reported in only few studies [87]. In fact, out of the 29 included randomized controlled exercise trials, only two studies reported exercise-related adverse events, with three patients experiencing muscle soreness and two patients suffering a musculoskeletal injury [87]. All remaining studies stated either that no adverse events were exercise-related or did not report those at all. The latter is  especially of concern, because reporting of adverse events systematically based on NCI Common Terminology Criteria for Adverse Events (CTCAE) is rare in exercise oncology related studies, implying that nearly all exercise regimens are safe in this population. However, this observation might be misleading due to limited reporting and evidence. This is for example underlined by a study assessing the effects of regular aerobic training in cancer patients with a concomitant stable heart failure, where the data indicated that all-cause mortality, as well as cardiovascular mortality and hospitalization, was higher at a 35 months follow-up in the training group as compared to the control group [52]. However, post-hoc analysis based on exercise adherence revealed that there was a higher risk for all-cause mortality and hospitalization in patients not adhering to the exercise volume of at least 90 min per week [52]. Based on the post-hoc analysis, it was concluded that supervised aerobic training might be safe and efficacious for patients able to adhere to the exercise prescription. This example clearly demonstrates that a thorough and detailed reporting of adverse events and adherence rates but also an individually tailored exercise prescription are warranted to conduct safe and efficient exercise programs.

Current Application of Exercise Prescription for Cancer Patients in Germany

The transition from research findings to clinical practice remains a significant challenge, similar in Germany. Empirical data have shown that it may take on average 17 years to translate even a small percentage of research into measurable practical outcomes [81]. The reasons for this gap between science and practice are manifold [25] but may include a lack of knowledge concerning evidence-based interventions, failure in understanding the need to introduce evidence-based exercise interventions, or barriers concerning the feasibility to integrate exercise programs within existing routines [22, 25]. It appears that many of these reasons are not specific to cancer but are much rather related to general practical aspects of implementation, requiring organization, sufficient expertise and funding [25]. While some of these aspects may not be directly influenced by research practices, factors concerning the research design should be considered. These often include research studies using exercise training protocols that are impractical to replicate or even impossible to implement in real-world healthcare settings [6] as well as a lack of data concerning dose–response relationships for clinically meaningful outcomes. It is obvious that this provides a significant challenge for us as scientists, to find the right balance between scientific rigor and practical applicability to further prove the effectiveness of exercise interventions in cancer patients and at the same time to improve the transition from lab to bedside.

The German healthcare system is a dual public–private system that foundation was laid by Otto von Bismarck in the 1880s, making it the oldest in Europe [40]. The system is considered a contribution-based social insurance, which is self-administered, decentralized and primarily funded by the public sector [40, 92]. Generally, it is based on four basic principles: (i) compulsory insurance; (ii) funding through insurance premiums; (iii) principle of solidarity and (iv) principle of self-governance [40, 92]. Following these principles, Germany guarantees healthcare to all citizens and, today, there are approximately 97% of the population insured in the public health insurance, while the majority of the remaining 3% are either covered by a private insurance or are in special arrangements for civil servants [92]. Contrary to other countries, the German system is not funded through general taxation but through sickness funds, which are financed by employees and employer payroll taxes. The principle of self-governance means that the federal government is not responsible for the organization of healthcare delivery but it shares responsibilities together with the 16 federal states for public health, including the management of hospitals and regulatory decisions [40, 92].

The federal joint committee is the independent authoritative for both appraisal and decision-making in the ambulatory and inpatient sectors [34, 92]. As such, the federal joint committee determines which medical care services are covered by the public health insurance and assesses the quality management and assurance of the medical services. Furthermore, the agency has the tasks to perform cost–benefit assessments and at the same time evaluates clinical practice guidelines, to submit recommendations on disease management for chronic diseases such as heart failure, diabetes and cancer. All these decisions and processes are based on the principles of evidence-based medicine [34, 92].

Considering the scientific evidence on beneficial exercise-induced effects across all stages of cancer prevention and treatment, it is obvious that exercise training has to be part of the usual care not only in Germany but also worldwide and, thus, should be covered by the health insurance systems. The evidence about the positive effects of exercise training for cancer patients has been reviewed, rated and incorporated in several German oncological guidelines (S3-Leitlinie) such as for mamma, prostate and hepatic carcinoma (Table 1) [3]. However, one has to bear in mind that in contrast to regulations, guidelines are not legally binding in Germany. Nevertheless, these guidelines provide a summary on the current medical knowledge, weigh the benefits and the harms of medical services, and provide detailed recommendations of potential proceedings.

Table 1 Overview of all available S3—guidelines for oncological treatment in Germany [3] with or without gathered and rated evidence about exercise training

However, despite the tremendous evidence, the federal joint committee has failed to include unified strategies of exercise oncology in the health insurance catalogue of covered medical services so far. Therefore, there is no uniform and nation-wide decision about the assumption of costs for measures of exercise oncology, contributing to the dilemma that exercise oncology is not yet part of the curriculum for medical students or therapists. Nevertheless, there are singularized attempts or alternatives to be aware off, such as medical device-based exercise [33] or medical doctor’s prescription for exercise [60]. The medical device-based exercise is covered by the public health insurance, however, the number of applications (prescription quantity) is not uniformly regulated and, thus, mainly depends on the physician as well as the severity of the symptoms [33]. The prescription for exercise, on the other hand, is an initiative of the German Olympic Sports Confederation, the Federal Medical Association and the German Association of Sports Medicine and Prevention. In contrast to the medical device-based exercise, the medical doctor’s prescription for exercise is not covered by the health insurance but has to be paid by the patient itself [60]. Importantly, both types of exercise prescription are dependent on the physician and his knowledge about these options as well as the beneficial effects of exercise in the treatment of cancer, highlighting the need for publically available research findings.

A third option for exercise prescription in the oncological treatment is the multidisciplinary oncological rehabilitation. This option is offered by both the health and pension insurance and the costs depend on the patient's status of retirement or employment [23]. The oncological rehabilitation can be administered immediately after hospital discharge, however, the outpatient or inpatient cancer treatment has to be completed. Furthermore certain medical requirements apply to the oncological rehabilitation, such as (i) the presence of an international classification of disease diagnoses (ICD), (ii) completion of the initial treatment (i.e. surgery or radiation therapy), (iii) treatability of the physical, mental, social or occupational disabilities, and (iv) sufficient resilience of the patient. In addition, certain administrative requirements have to be fulfilled such as six month of compulsory contribution within the last two years [23]. On average, the duration of an oncological rehabilitation is three weeks and includes a personal surcharge of 10 Euro per day. In addition to this singularized but nationwide available options, there are local attempts to provide free training, often in collaboration with nationally arranged experts groups.

Overall, the current options for cancer patients to benefit from exercise oncology services are rather short-dated and, thus, a tailored exercise prescription including a progressive and structured (i.e. periodized) exercise regimen is difficult to implement. This is in contrast to the overwhelming evidence that clearly indicates that such exercise programs are needed to counteract both, short-term and long-term side effects of the disease and/or its treatment. However, we believe that the recent comprehensive national and international research attempts provide an immense potential to improve the care of cancer patients during all stages of the cancer control continuum in the near future. As such, we also appeal to the German healthcare system to implement and guarantee a nation-wide system for structured exercise oncology.

Conclusion

Although the understanding of exercise prescription for the prevention and treatment of cancer has further improved over the past decades, tailored exercise prescription and periodization remains a rare phenomenon. The reasons for that are manifold but are often related to a combination of infrastructural shortages as well as knowledge gaps. To further facilitate the transfer of exercise interventions into the practice of cancer therapy, it is of utmost importance that studies go beyond simple feasibility and compliance outcomes and are performed with rigor designs (phase III and IV studies). This does not only include a homogenous study population and sufficient sample size but much rather also the inclusion of well-designed and structured training programs, targeting clinically relevant outcomes (such as overall survival), while concomittantly elucidating the underlying mechanisms. This is a key concern because in previous studies different types of training (e.g. aerobic and strength training) but also different training modes and intensity characteristics were often merged. Obviously, this facilitates recruitment of patients and reception of ethics approval but at the same time, these approaches may hinder both the interpretation and generalizability of the study results, especially considering the persistent disease-related heterogeneity in oncology. To overcome this, we suggest an even closer link between exercise science professionals and clinical oncologists. Consequently, basic methodological exercise research performed with healthy participants will build a solid base by exposing possible mechanisms, which may be relevant to counteract the pathogenesis of cancer and/or cancer treatment. These exercise regimens may then be transferred into clinical trials, verifying that the hypothesized outcome may indeed be achieved.

References

  1. 1.

    Ahtiainen JP, Walker S, Peltonen H, Holviala J, Sillanpää E, Karavirta L, Sallinen J, Mikkola J, Valkeinen H, Mero A, Hulmi JJ, Häkkinen K. Heterogeneity in resistance training-induced muscle strength and mass responses in men and women of different ages. Age (Omaha). 2016;38(1):1–13. https://doi.org/10.1007/s11357-015-9870-1.

    Article  Google Scholar 

  2. 2.

    Araujo AB, Esche GR, Kupelian V, O’Donnell AB, Travison TG, Williams RE, Clark RV, McKinlay JB. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92(11):4241–7. https://doi.org/10.1210/jc.2007-1245.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V., Deutsche Krebsgesellschaft e.V., Deutsche Krebshilfte Leitlinienprogramm Onkologie: Informationen zum Leitlinienprogramm. https://www.leitlinienprogramm-onkologie.de/programm/informationen-zum-leitlinienprogramm/. Accessed 21 Apr 2020.

  4. 4.

    Ashcraft KA, Warner AB, Jones LW, Dewhirst MW. Exercise as adjunct therapy in cancer. Semin Radiat Oncol. 2019;29(1):16–24.

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Bandak M, Jørgensen N, Juul A, Vogelius IR, Lauritsen J, Kier MG, Mortensen MS, Glovinski P, Daugaard G. Testosterone deficiency in testicular cancer survivors—a systematic review and meta-analysis. Andrology. 2016;4(3):382–8. https://doi.org/10.1111/andr.12177.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Beedie C, Mann S, Jimenez A, Kennedy L, Lane AM, Domone S, Wilson S, Whyte G. Death by effectiveness: exercise as medicine caught in the efficacy trap! Br J Sports Med. 2016;50(6):323–4.

    PubMed  Article  Google Scholar 

  7. 7.

    Betof AS, Dewhirst MW, Jones LW. Effects and potential mechanisms of exercise training on cancer progression: a translational perspective. Brain Behav Immun. 2013;30:S75–87.

    PubMed  Article  Google Scholar 

  8. 8.

    Betof AS, Lascola CD, Weitzel D, Landon C, Scarbrough PM, Devi GR, Palmer G, Jones LW, Dewhirst MW. Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise. J Natl Cancer Inst. 2015;107:djv040. https://doi.org/10.1093/jnci/djv040.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Bloomquist K, Adamsen L, Hayes SC, Lillelund C, Andersen C, Christensen KB, Oturai P, Ejlertsen B, Tuxen MK, Møller T. Heavy-load resistance exercise during chemotherapy in physically inactive breast cancer survivors at risk for lymphedema: a randomized trial. Acta Oncol (Madr). 2019;58(12):1667–755. https://doi.org/10.1080/0284186X.2019.1643916.

    CAS  Article  Google Scholar 

  10. 10.

    Bouchard C, An P, Rice T, Skinner JS, Wilmore JH, Gagnon J, Pérusse L, Leon AS, Rao DC. Familial aggregation of V̇O(2max) response to exercise training: results from the HERITAGE family study. J Appl Physiol. 1999;87(3):1003–8. https://doi.org/10.1152/jappl.1999.87.3.1003.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Braspenning I, Tamminga S, Frings-Dresen MHW, Leensen M, Boer A de, Tikka C, Verbeek JH, Munir F, Garton S, Amir Z, Smith L, Sharp L, Haste A. Rehabilitation and return to work after cancer—instruments and practices. 2018. https://hdl.handle.net/2134/33414.

  12. 12.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.

    PubMed  Article  Google Scholar 

  13. 13.

    Brooks GA. Cell-cell and intracellular lactate shuttles. J Physiol. 2009;587:5591–600.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Campbell KL, Winters-Stone KM, Wiskemann J, May AM, Schwartz AL, Courneya KS, Zucker DS, Matthews CE, Ligibel JA, Gerber LH, Morris GS, Patel AV, Hue TF, Perna FM, Schmitz KH. Exercise guidelines for cancer survivors: consensus statement from international multidisciplinary roundtable. Med Sci Sports Exerc. 2019;51(11):2375–90. https://doi.org/10.1249/MSS.0000000000002116.

    PubMed  Article  Google Scholar 

  15. 15.

    Centemero A, Rigatti L, Giraudo D, Lazzeri M, Lughezzani G, Zugna D, Montorsi F, Rigatti P, Guazzoni G. Preoperative pelvic floor muscle exercise for early continence after radical prostatectomy: a randomised controlled study. Eur Urol. 2010;57(6):1039–44. https://doi.org/10.1016/j.eururo.2010.02.028.

    PubMed  Article  Google Scholar 

  16. 16.

    Chen Z, Zhang Y, Lu C, Zeng H, Schumann M, Cheng S. Supervised physical training enhances muscle strength but not muscle mass in prostate cancer patients undergoing androgen deprivation therapy: a systematic review and meta-analysis. Front Physiol. 2019;10:843. https://doi.org/10.3389/fphys.2019.00843.

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Christensen JF, Simonsen C, Hojman P. Exercise training in cancer control and treatment. Compr Physiol. 2018;9:165–205.

    PubMed  Article  Google Scholar 

  18. 18.

    Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372(9):793–5. https://doi.org/10.1056/NEJMp1500523.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Cormie P, Atkinson M, Bucci L, Cust A, Eakin E, Hayes S, McCarthy S, Murnane A, Patchell S, Adams D. Clinical oncology society of Australia position statement on exercise in cancer care. Med J Aust. 2018;209:184–7. https://doi.org/10.5694/mja18.00199.

    PubMed  Article  Google Scholar 

  20. 20.

    Courneya KS, Friedenreich CM. Physical activity and cancer control. Semin Oncol Nurs. 2007;23(4):242–52. https://doi.org/10.1016/j.soncn.2007.08.002.

    PubMed  Article  Google Scholar 

  21. 21.

    Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev. 2012. https://doi.org/10.1002/14651858.CD006145.pub3.

    PubMed  Article  Google Scholar 

  22. 22.

    Czosnek L, Rankin N, Zopf E, Richards J, Rosenbaum S, Cormie P. Implementing exercise in healthcare settings: the potential of implementation science. Sport Med. 2020;50(1):1–14. https://doi.org/10.1007/s40279-019-01228-0.

    Article  Google Scholar 

  23. 23.

    Deutsche Rentenversicherung. DRV—Onkologische Reha—Onkologische Reha. 2020. https://www.deutsche-rentenversicherung.de/DRV/DE/Reha/Medizinische-Reha/Onkologische-Reha/onkologische-reha.html. Accessed 10 Apr 2020.

  24. 24.

    Duregon F, Vendramin B, Bullo V, Gobbo S, Cugusi L, Di Blasio A, Neunhaeuserer D, Zaccaria M, Bergamin M, Ermolao A. Effects of exercise on cancer patients suffering chemotherapy-induced peripheral neuropathy undergoing treatment: a systematic review. Crit Rev Oncol Hematol. 2018;121:90–100.

    PubMed  Article  Google Scholar 

  25. 25.

    Durlak JA, DuPre EP. Implementation matters: a review of research on the influence of implementation on program outcomes and the factors affecting implementation. Am J Community Psychol. 2008;41(3-4):327–50. https://doi.org/10.1007/s10464-008-9165-0.

    PubMed  Article  Google Scholar 

  26. 26.

    Eschke RCKR, Lampit A, Schenk A, Javelle F, Steindorf K, Diel P, Bloch W, Zimmer P. Impact of physical exercise on growth and progression of cancer in rodents—a systematic review and meta-analysis. Front Oncol. 2019;9:35.

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Fairman CM, Nilsen TS, Newton RU, Taaffe DR, Spry N, Joseph D, Chambers SK, Robinson ZP, Hart NH, Zourdos MC, Focht BC, Peddle-Mcintyre CJ, Galvaõ DA. Reporting of resistance training dose, adherence, and tolerance in exercise oncology. Med Sci Sports Exerc. 2020;52(2):315–22. https://doi.org/10.1249/MSS.0000000000002127.

    PubMed  Article  Google Scholar 

  28. 28.

    Fletcher GF, Landolfo C, Niebauer J, Ozemek C, Arena R, Lavie CJ. Promoting physical activity and exercise: JACC health promotion series. J Am Coll Cardiol. 2018;72(23):1622–39.

    PubMed  Article  Google Scholar 

  29. 29.

    Freitag N, Weber PD, Sanders TC, Schulz H, Bloch W, Schumann M. High-intensity interval training and hyperoxia during chemotherapy. A case report about the feasibility, safety and physical functioning in a colorectal cancer patient. Medicine (United States). 2018;97:e11068. https://doi.org/10.1097/MD.0000000000011068.

    Article  Google Scholar 

  30. 30.

    Friedenreich CM, Shaw E, Neilson HK, Brenner DR. Epidemiology and biology of physical activity and cancer recurrence. J Mol Med. 2017;95(10):1029–41.

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Galvão DA, Spry NA, Taaffe DR, Newton RU, Stanley J, Shannon T, Rowling C, Prince R. Changes in muscle, fat and bone mass after 36 weeks of maximal androgen blockade for prostate cancer. BJU Int. 2008;102(1):44–7. https://doi.org/10.1111/j.1464-410X.2008.07539.x.

    PubMed  Article  Google Scholar 

  32. 32.

    Garber CE, Blissmer B, Deschenes MR, Franklin BA, Lamonte MJ, Lee IM, Nieman DC, Swain DP. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med Sci Sports Exerc. 2011;43(7):1334–59. https://doi.org/10.1249/MSS.0b013e318213fefb.

    PubMed  Article  Google Scholar 

  33. 33.

    Bundesausschuss G. Heilmittel-Richtlinie. Gemeinsamer Bundesausschuss. 2011;96:1–30.

    Google Scholar 

  34. 34.

    Gemeinsamer Bundesausschuss. Aufgabe und Arbeitsweise. 2019. https://www.g-ba.de/ueber-den-gba/aufgabe-arbeitsweise/. Accessed 9 Apr 2020.

  35. 35.

    Gerritsen JKW, Vincent AJPE. Exercise improves quality of life in patients with cancer: a systematic review and meta-analysis of randomised controlled trials. Br J Sports Med. 2016;50(13):796–803.

    PubMed  Article  Google Scholar 

  36. 36.

    Gil-Rey E, Quevedo-Jerez K, Maldonado-Martin S, Herrero-Román F. Exercise intensity guidelines for cancer survivors: a comparison with reference values. Int J Sports Med. 2014;35(14):e1–e9. https://doi.org/10.1055/s-0034-1389972.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Godlee F. The miracle cure. BMJ. 2019;366:l5759. https://doi.org/10.1136/bmj.l5759.

    Article  Google Scholar 

  38. 38.

    Goodwin ML, Jin H, Straessler K, Smith-Fry K, Zhu JF, Monument MJ, Grossmann A, Randall RL, Capecchi MR, Jones KB. Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment. Cancer Cell. 2014;26(6):851–62. https://doi.org/10.1016/j.ccell.2014.10.003.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Goodwin ML, Pennington Z, Westbroek EM, Cottrill E, Ahmed AK, Sciubba DM. Lactate and cancer: a “lactatic” perspective on spinal tumor metabolism (part 1). Ann Transl Med. 2019;7(10):220–220. https://doi.org/10.21037/atm.2019.02.32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Graf von der Schulenburg JM, Uber A. Current issues in German healthcare. Pharmacoeconomics. 1997;12(5):517–23. https://doi.org/10.2165/00019053-199712050-00002.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Hallal PC, Andersen LB, Bull FC, Guthold R, Haskell W, Ekelund U, Alkandari JR, Bauman AE, Blair SN, Brownson RC, Craig CL, Goenka S, Heath GW, Inoue S, Kahlmeier S, Katzmarzyk PT, Kohl HW, Lambert EV, Lee IM, Leetongin G, Lobelo F, Loos RJF, Marcus B, Martin BW, Owen N, Parra DC, Pratt M, Puska P, Ogilvie D, Reis RS, Sallis JF, Sarmiento OL, Wells JC. Global physical activity levels: surveillance progress, pitfalls, and prospects. Lancet. 2012;380(9838):247–57.

    PubMed  Article  Google Scholar 

  42. 42.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. https://doi.org/10.1016/j.cell.2011.02.013.

    CAS  Article  Google Scholar 

  43. 43.

    Hart NH, Galvão DA, Newton RU. Exercise medicine for advanced prostate cancer. Curr Opin Support Palliat Care. 2017;11:247–57.

    PubMed  Article  Google Scholar 

  44. 44.

    Hassoon A, Schrack J, Naiman D, Lansey D, Baig Y, Stearns V, Celentano D, Martin S, Appel L. Increasing physical activity amongst overweight and obese cancer survivors using an alexa-based intelligent agent for patient coaching: protocol for the physical activity by technology help (path) trial. J Med Internet Res. 2018;7(2):e27. https://doi.org/10.2196/resprot.9096.

    Article  Google Scholar 

  45. 45.

    Hayes SC, Newton RU, Spence RR, Galvão DA. The Exercise and Sports Science Australia position statement: exercise medicine in cancer management. J Sci Med Sport. 2019;22(11):1175–99.

    PubMed  Article  Google Scholar 

  46. 46.

    Hayes SC, Spence RR, Galvão DA, Newton RU. Australian Association for Exercise and Sport Science position stand: optimising cancer outcomes through exercise. J Sci Med Sport. 2009;12(4):428–34.

    PubMed  Article  Google Scholar 

  47. 47.

    Henry DH, Viswanathan HN, Elkin EP, Traina S, Wade S, Cella D. Symptoms and treatment burden associated with cancer treatment: results from a cross-sectional national survey in the U.S. Support Care Cancer. 2008;16(7):791–801. https://doi.org/10.1007/s00520-007-0380-2.

    PubMed  Article  Google Scholar 

  48. 48.

    Hermann S, Friedrich S, Arndt V. Aktuelle Entwicklungen der Krebsinzidenz und Mortalität in Deutschland. Best Pract Onkol. 2016;11(3–4):38–45. https://doi.org/10.1007/s11654-016-0583-4.

    Article  Google Scholar 

  49. 49.

    Hofmann P. Cancer and exercise: Warburg Hypothesis, tumour metabolism and high-intensity anaerobic exercise. Sports. 2018;6(1):10. https://doi.org/10.3390/sports6010010.

    PubMed Central  Article  Google Scholar 

  50. 50.

    Hollidge-Horvat MG, Parolin ML, Wong D, Jones NL, Heigenhauser GJF. Effect of induced metabolic acidosis on human skeletal muscle metabolism during exercise. Am J Physiol Endocrinol Metab. 1999;277(4):E647–58. https://doi.org/10.1152/ajpendo.1999.277.4.e647.

    CAS  Article  Google Scholar 

  51. 51.

    Idorn M, thor-Straten P. Exercise and cancer: from “healthy” to “therapeutic”? Cancer Immunol Immunother. 2017;66(5):667–71.

    PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Jones LW, Douglas PS, Khouri MG, Mackey JR, Wojdyla D, Kraus WE, Whellan DJ, O’Connor CM. Safety and efficacy of aerobic training in patients with cancer who have heart failure: an analysis of the HF-ACTION randomized trial. J Clin Oncol. 2014;32(23):2496–502. https://doi.org/10.1200/JCO.2013.53.5724.

    PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Jones LW, Liang Y, Pituskin EN, Battaglini CL, Scott JM, Hornsby WE, Haykowsky M. Effect of exercise training on peak oxygen consumption in patients with cancer: a meta-analysis. Oncologist. 2011;16(1):112–20. https://doi.org/10.1634/theoncologist.2010-0197.

    PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Kelley GA, Kelley KS. Exercise and cancer-related fatigue in adults: a systematic review of previous systematic reviews with meta-analyses. BMC Cancer. 2017;17(1):693. https://doi.org/10.1186/s12885-017-3687-5.

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Kirkham AA, Bland KA, Zucker DS, Bovard J, Shenkier T, McKenzie DC, Davis MK, Gelmon KA, Campbell KL. “Chemotherapy-periodized” Exercise to Accommodate for Cyclical Variation in Fatigue. Med Sci Sports Exerc. 2020;52(2):278–86. https://doi.org/10.1249/MSS.0000000000002151.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Koelwyn GJ, Quail DF, Zhang X, White RM, Jones LW. Exercise-dependent regulation of the tumour microenvironment. Nat Rev Cancer. 2017;17(10):620–32.

    PubMed  Article  Google Scholar 

  57. 57.

    Kwan ML, Cohn JC, Armer JM, Stewart BR, Cormier JN. Exercise in patients with lymphedema: a systematic review of the contemporary literature. J Cancer Surviv. 2011;5:320–36.

    PubMed  Article  Google Scholar 

  58. 58.

    de la Cruz-López KG, Castro-Muñoz LJ, Reyes-Hernández DO, García-Carrancá A, Manzo-Merino J. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front. Oncol. 2019;9:1143. https://doi.org/10.3389/fonc.2019.01143.

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Limpawattana P, Theerakulpisut D, Wirasorn K, Sookprasert A, Khuntikeo N, Chindaprasirt J. The impact of skeletal muscle mass on survival outcome in biliary tract cancer patients. PLoS ONE. 2018;13:e0204985. https://doi.org/10.1371/journal.pone.0204985.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Löllgen H, Wismach J, Kunstmann W. Exercise prescription for health—benefit for practitioner and patients. Klinikarzt. 2013;42:416–20. https://doi.org/10.1055/s-0033-1358596.

    Article  Google Scholar 

  61. 61.

    Loud JT, Murphy J. Cancer screening and early detection in the 21st Century. Semin Oncol Nurs. 2017;33(2):121–8.

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    McLaughlin M, Jacobs I. Exercise is medicine, but does it interfere with medicine? Exerc Sport Sci Rev. 2017;45(3):127–35.

    PubMed  Article  Google Scholar 

  63. 63.

    Mijwel S, Backman M, Bolam KA, Olofsson E, Norrbom J, Bergh J, Sundberg CJ, Wengström Y, Rundqvist H. Highly favorable physiological responses to concurrent resistance and high-intensity interval training during chemotherapy: the OptiTrain breast cancer trial. Breast Cancer Res Treat. 2018;169(1):93–103. https://doi.org/10.1007/s10549-018-4663-8.

    PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Mijwel S, Jervaeus A, Bolam KA, Norrbom J, Bergh J, Rundqvist H, Wengström Y. High-intensity exercise during chemotherapy induces beneficial effects 12 months into breast cancer survivorship. J Cancer Surviv. 2019;13:244–56. https://doi.org/10.1007/s11764-019-00747-z.

    PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Mohandas H, Jaganathan SK, Mani MP, Ayyar M, Rohini Thevi GV. Cancer-related fatigue treatment: an overview. J Cancer Res Ther. 2017;13(6):916–29.

    PubMed  Google Scholar 

  66. 66.

    Mugele H, Freitag N, Wilhelmi J, Yang Y, Cheng S, Bloch W, Schumann M. High-intensity interval training in the therapy and aftercare of cancer patients: a systematic review with meta-analysis. J Cancer Surviv. 2019;13:205–23.

    PubMed  Article  Google Scholar 

  67. 67.

    NCT03066271. Pre radiotherapy daily exercise training in non-small cell lung cancer (PRIME). 2017. https://clinicaltrials.gov/ct2/show/NCT03066271. Accessed 10 Apr 2020.

  68. 68.

    NCT04119778. Improving survival in lung cancer patients: a trial of aerobic exercise and tai-chi. 2019. https://clinicaltrials.gov/ct2/show/NCT04119778. Accessed Apr 2020.

  69. 69.

    NCT04120298. ffects of exercise in patients with metastatic breast cancer (EFFECT). 2019. https://clinicaltrials.gov/ct2/show/NCT04120298. Accessed 10 Apr 2020.

  70. 70.

    Newton RU, Kenfield SA, Hart NH, Chan JM, Courneya KS, Catto J, Finn SP, Greenwood R, Hughes DC, Mucci L, Plymate SR, Praet SFE, Guinan EM, Van Blarigan EL, Casey O, Buzza M, Gledhill S, Zhang L, Galvão DA, Ryan CJ, Saad F. Intense Exercise for survival among men with metastatic castrate-resistant prostate cancer (INTERVAL-GAP4): a multicentre, randomised, controlled phase III study protocol. BMJ Open. 2018;8(5):e022899. https://doi.org/10.1136/bmjopen-2018-022899.

    PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    De Palma M, Hanahan D. The biology of personalized cancer medicine: facing individual complexities underlying hallmark capabilities. Mol Oncol. 2012;6(2):111–27.

    PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Patel AV, Friedenreich CM, Moore SC, Hayes SC, Silver JK, Campbell KL, Winters-Stone K, Gerber LH, George SM, Fulton JE, Denlinger C, Morris GS, Hue T, Schmitz KH, Matthews CE. American College of Sports Medicine Roundtable Report on physical activity, sedentary behavior, and cancer prevention and control. Med Sci Sports Exerc. 2019;51(11):2391–402. https://doi.org/10.1249/MSS.0000000000002117.

    PubMed  Article  Google Scholar 

  73. 73.

    Pedersen BK, Saltin B. Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports. 2015;25:1–72. https://doi.org/10.1111/sms.12581.

    PubMed  Article  Google Scholar 

  74. 74.

    Racker E. Bioenergetics and the problem of tumor growth. Am Sci. 1972;60(1):56–63.

    CAS  PubMed  Google Scholar 

  75. 75.

    Ramírez-Vélez R, Lobelo F, Izquierdo M. Exercise for disease prevention and management: a precision medicine approach. J Am Med Dir Assoc. 2017;18(7):633–4.

    PubMed  Article  Google Scholar 

  76. 76.

    Riebe D, Franklin BA, Thompson PD, Garber CE, Whitfield GP, Magal M, Pescatello LS. Updating ACSM’s recommendations for exercise preparticipation health screening. Med Sci Sports Exerc. 2015;47(11):2473–9. https://doi.org/10.1249/MSS.0000000000000664.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Ritvo P, Obadia M, Santa Mina D, Alibhai S, Sabiston C, Oh P, Campbell K, McCready D, Auger L, Jones JM. Smartphone-Enabled Health Coaching Intervention (iMOVE) to promote long-term maintenance of physical activity in breast cancer survivors: protocol for a feasibility pilot randomized controlled trial. JMIR Res Protoc. 2017;6(8):e165. https://doi.org/10.2196/resprot.6615.

    PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Ross R, Goodpaster BH, Koch LG, Sarzynski MA, Kohrt WM, Johannsen NM, Skinner JS, Castro A, Irving BA, Noland RC, Sparks LM, Spielmann G, Day AG, Pitsch W, Hopkins WG, Bouchard C. Precision exercise medicine: understanding exercise response variability. Br J Sports Med. 2019;53(18):1141–53. https://doi.org/10.1136/bjsports-2018-100328.

    PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Rossen S, Kayser L, Vibe-Petersen J, Ried-Larsen M, Christensen JF. Technology in exercise-based cancer rehabilitation: a cross-sectional study of receptiveness and readiness for e-Health utilization in Danish cancer rehabilitation. Acta Oncol (Madr). 2019;58(5):610–8. https://doi.org/10.1080/0284186X.2018.1562213.

    Article  Google Scholar 

  80. 80.

    Ruiz-Casado A, Martín-Ruiz A, Pérez LM, Provencio M, Fiuza-Luces C, Lucia A. Exercise and the hallmarks of cancer. Trends in Cancer. 2017;3:423–41.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Sackett DL. Evidence-based medicine. Seminars in perinatology. Philadelphia: W.B. Saunders; 1997. p. 3–5.

    Google Scholar 

  82. 82.

    Sallis RE. Exercise is medicine and physicians need to prescribe it! Br. J Sports Med. 2009;43(1):3–4.

    CAS  Google Scholar 

  83. 83.

    Schmitz KH, Campbell AM, Stuiver MM, Pinto BM, Schwartz AL, Morris GS, Ligibel JA, Cheville A, Galvão DA, Alfano CM, Patel AV, Hue T, Gerber LH, Sallis R, Gusani NJ, Stout NL, Chan L, Flowers F, Doyle C, Helmrich S, Bain W, Sokolof J, Winters-Stone KM, Campbell KL, Matthews CE. Exercise is medicine in oncology: engaging clinicians to help patients move through cancer. CA Cancer J Clin. 2019;69(6):468–84. https://doi.org/10.3322/caac.21579.

    PubMed  Article  Google Scholar 

  84. 84.

    Schmitz KH, Courneya KS, Matthews C, Demark-Wahnefried W, Galvão DA, Pinto BM, Irwin ML, Wolin KY, Segal RJ, Lucia A, Schneider CM, Von Gruenigen VE, Schwartz AL. American college of sports medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42(7):1409–26.

    PubMed  Article  Google Scholar 

  85. 85.

    Schrack JA, Gresham G, Wanigatunga AA. Understanding physical activity in cancer patients and survivors: new methodology, new challenges, and new opportunities. Cold Spring Harb Mol Case Stud. 2017;3(4):a001933.

    PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Scott JM, Nilsen TS, Gupta D, Jones LW. Exercise therapy and cardiovascular toxicity in cancer. Circulation. 2018;137(11):1176–91. https://doi.org/10.1161/CIRCULATIONAHA.117.024671.

    PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Segal R, Zwaal C, Green E, Tomasone J, Loblaw A, Petrella T. Exercise for people with cancer: recommendations summary. Curr Oncol. 2017;24(1):e290–315. https://doi.org/10.3747/co.24.3619.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Sheill G, Guinan EM, Peat N, Hussey J. Considerations for exercise prescription in patients with bone metastases: a comprehensive narrative review. PM&R. 2018;10(8):843–64.

    Article  Google Scholar 

  89. 89.

    Smallbone K, Maini PK, Gatenby RA. Episodic, transient systemic acidosis delays evolution of the malignant phenotype: possible mechanism for cancer prevention by increased physical activity. Biol Direct. 2010;5:22. https://doi.org/10.1186/1745-6150-5-22.

    PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Stefani L, Galanti G, Klika R. Clinical implementation of exercise guidelines for cancer patients: adaptation of ACSM’s guidelines to the Italian model. J Funct Morphol Kinesiol. 2017;2(1):4. https://doi.org/10.3390/jfmk2010004.

    Article  Google Scholar 

  91. 91.

    Strasser B, Steindorf K, Wiskemann J, Ulrich CM. Impact of resistance training in cancer survivors: a meta-analysis. Med Sci Sports Exerc. 2013;45(11):2080–90. https://doi.org/10.1249/MSS.0b013e31829a3b63.

    PubMed  Article  Google Scholar 

  92. 92.

    The Economist Intelligence Unit. Value-based Healthcare in Germany From free price-setting to a regulated market. 2015. https://eiuperspectives.economist.com/healthcare/value-based-healthcare-germany-free-price-setting-regulated-market. Accessed 10 Apr 2020.

  93. 93.

    Tipton CM. History of Exercise Physiology. Human Kinetics. 2014. https://us.humankinetics.com/products/history-of-exercise-physiology-pdf.

  94. 94.

    Twomey R, Yeung ST, Wrightson JG, Millet GY, Culos-Reed SN. Post-exertional malaise in people with chronic cancer-related fatigue. J Pain Symptom Manag. 2020;60(2):407–16. https://doi.org/10.1016/j.jpainsymman.2020.02.012.

    Article  Google Scholar 

  95. 95.

    Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14. https://doi.org/10.1126/science.123.3191.309.

    CAS  Article  Google Scholar 

  96. 96.

    Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519–30. https://doi.org/10.1085/jgp.8.6.519.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    West HJ. Complementary and alternative medicine in cancer care. JAMA Oncol. 2018;4(1):139.

    PubMed  Article  Google Scholar 

  98. 98.

    World Health Organization. Physical activity: global recommendations on physical activity for health consequences of physical inactivity. Geneva: World Health Organization; 2010.

    Google Scholar 

  99. 99.

    Zarrinpar A, Lee DK, Silva A, Datta N, Kee T, Eriksen C, Weigle K, Agopian V, Kaldas F, Farmer D, Wang SE, Busuttil R, Ho CM, Ho D. Individualizing liver transplant immunosuppression using a phenotypic personalized medicine platform. Sci Transl Med. 2016;8:333ra49. https://doi.org/10.1126/scitranslmed.aac5954.

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Zeng J, Wu J, Tang C, Xu N, Lu L. Effects of exercise during or postchemotherapy in cancer patients: a systematic review and meta-analysis. Worldviews Evidence-Based Nurs. 2019;16(2):92–101. https://doi.org/10.1111/wvn.12341.

    Article  Google Scholar 

Download references

Acknowledgements

Open Access funding provided by Projekt DEAL. The authors have no acknowledgements to declare.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Affiliations

Authors

Contributions

MS, NF and WB contributed to the design of the draft and the literature search as well as the manuscript writing and editing.

Corresponding author

Correspondence to Moritz Schumann.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Approval

This manuscript does not contain any studies with human participants or animal subjects performed by any of the authors.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schumann, M., Freitag, N. & Bloch, W. Advanced Exercise Prescription for Cancer Patients and its Application in Germany. J. of SCI. IN SPORT AND EXERCISE 2, 201–214 (2020). https://doi.org/10.1007/s42978-020-00074-1

Download citation

Keywords

  • Exercise medicine
  • Clinical exercise science
  • Exercise guidelines
  • Exercise therapy
  • Exercise oncology