Introduction

A cancer diagnosis is commonly accompanied by progressive physiological and psychosocial deterioration due to disease manifestation and the adverse effects of treatment. A convincing body of evidence has led to a general acceptance that exercise is a viable strategy of enhancing physical and psychosocial outcomes in individuals with cancer. Moreover, epidemiological evidence demonstrates that exercise reduces the risk of cancer recurrence and mortality [1]. The mechanistic properties of these relationships have been explored via in vitro models indicating exercise-related inhibitory effects on tumor growth and proliferation [2]. The antineoplastic effects of exercise are multifactorial and include reduced bioavailability of tumor growth factors [2], increases in p53 tumor suppressor protein [3], as well as natural killer cell mobilization and infiltration induced by epinephrine [4]. The overall evidence of benefits has underscored recommendations for exercise in people with cancer, most commonly delivered via moderate-intensity continuous training (MICT) that has established safety and effectiveness [5, 6]. However, growing research shows that exercising at higher intensities may offer different and/or additional benefits for people with cancer [7, 8]. Below, the physiological rationale for high-intensity interval training (HIIT) as a clinical tool in cancer care is introduced.

What is HIIT?

HIIT comprises a series of repeated bursts of high-intensity exercise, defined as 85–95% of peak heart rate, interspersed by periods of rest or active recovery (i.e., exercise at a lower intensity) [9]. Although most studies describe the intensity of HIIT protocols using percent of ‘maximum heart rate,’ ‘peak heart rate’ may be more precise if true physiological maximum cannot be ascertained during baseline testing. There are several forms of HIIT that vary the number and duration of the interval–recovery ratios yielding low- and high-volume protocols [7, 8]. The flexibility of HIIT protocols permits accommodation to the full range of fitness levels. While conventionally performed on a stationary cycle or treadmill, HIIT can be performed using modalities to match aerobic training preferences. Perhaps, the most advantageous aspect of HIIT from an implementation and adherence perspective is that it appears to maximize the exercise ‘dose’ in a short duration making it a time-efficient strategy for achieving cardiorespiratory fitness gains [7, 10]. For these reasons, HIIT has become an increasingly popular training strategy in the general population [11]. For individuals with cancer, the brevity of HIIT may be a preferred strategy for routine exercise to obviate common time-related barriers, such as medical appointments, returning to work, and daily windows of adequate energy. Beyond adherence, HIIT’s unique capacity to attenuate persistent inflammatory processes that are involved in cancer initiation and progression is particularly intriguing for the cancer clinician [12, 13].

HIIT, MICT, and their comparative roles in the chronic inflammatory response

Currently, no studies have directly compared the anti-inflammatory effects of HIIT versus MICT in cancer; however, such comparisons in other clinical populations indicate that HIIT may be more effective. Interleukin-6 (IL-6) is a pleiotropic cytokine with growth properties that promote tumor progression [12, 14]. While not studied in patients with cancer specifically, 12 weeks of HIIT significantly suppressed the plasma levels of IL-6 in patients with heart failure compared to MICT [13]. Another phenomenon that potentiates tumor growth and upregulates inflammation is the overexpression of reactive oxygen species (ROS) generated by persistent inflammatory reactions [15]. HIIT appears to moderate this pathway compared to MICT by increasing glutathione peroxidase (GPx) [16], an enzyme with protective effects against ROS [15] and therapeutic potential for several malignancies [17, 18]. Moreover, chronic expression of pro-inflammatory factors along with ROS facilitates insulin resistance [19] that can further promote tumor progression via increased production of the mitogenic insulin-like growth factors (IGFs) [19]. Meta-analytic evidence supports that insulin resistance is better regulated via HIIT compared to MICT [20] while some of the prevailing HIIT mechanisms responsible for the normalization of insulin activity involve increases in muscle mitochondrial biogenesis and glucose transporter 4 (GLUT4) protein [21]. Collectively, the aforementioned findings favor HIIT over MICT in fostering homeostatic processes that may play a therapeutic role in tumor control via mitigation of systemic and chronic inflammation.

The anti-inflammatory benefits of HIIT are also important for cardioprotection in patients at high risk of treatment-related cardiotoxicity [22]. These benefits are mediated by greater increases in cardiorespiratory fitness and reductions in cardiovascular risk factors in HIIT compared to MICT [7,8,9,10]. Moreover, promising evidence supports that HIIT significantly enhances antioxidant status and flow-mediated dilation compared to MICT in patients with heart failure [23]. This likely achieved through increasing production of nitric oxide [23] that has relevance in combatting chemotherapy-induced increases in ROS—one of the primary mechanisms contributing to cardiotoxicity in cancer patients [24]. Collectively, the effect of HIIT on cardiorespiratory fitness, endothelial function, and ROS to prevent or mitigate treatment-related cardiotoxicity is compelling and requires further investigation.

Safety of HIIT for people with cancer

Evidence indicates that HIIT can be safely performed in people with cancer [7, 8, 25,26,27,28,29,30,31,32]. In the ten studies that have conducted HIIT in a total of 522 people with cancer, one serious adverse event was reported (Table 1). In a randomized controlled trial (RCT) of mixed cancer diagnoses undergoing HIIT and resistance training or usual care, Adamsen and colleagues reported a grade 3 seizure following a HIIT session in a participant with brain cancer [26]. The participant was discharged on the same day and the authors suggest that patients with brain tumors or brain metastases should avoid high-intensity training [26]. Two additional nonsevere adverse events following HIIT (symptomatic hypotension) were reported in colorectal survivors in an RCT conducted by Devin et al. [7]. Despite these episodes, both participants completed the study. Midtgaard et al. found that six participants developed lymphedema over 12 months of HIIT and resistance training versus no adverse events in the control group [30]. It is unclear whether these symptoms were attributable to HIIT or resistance training; however, all six participants completed the intervention without additional symptoms [30]. While the current volume of data suggest that HIIT is safe in a variety of cancers, we support recommendations by Adamsen et al. for screening prior to each HIIT session to detect abnormalities and/or respond to fluctuations in health status [26]. This is especially important given that exercising at very high intensities may lead to temporary suppression of specific immune factors [33] that could cause further complications to individuals with abnormal blood parameters and compromised immune system.

Table 1 HIIT protocols and potentially attributable adverse effects in cancer survivors
Full size table

Conclusion and recommendations for future research

Accumulating evidence supports that HIIT mitigates inflammation directly or via its effects on oxidative stress and insulin resistance. These effects are of vital importance in oncology given the relationship between inflammation and tumor growth. Moreover, the anti-inflammatory effect of HIIT may help protect against cardiotoxicity associated with several types of cancer treatment that can lead to cardiovascular disease and mortality. The role of HIIT in cancer survivorship will be significantly advanced through investigations of the following key areas. First, there is a need to establish whether HIIT can effectively prevent and/or attenuate persistent inflammatory states in the oncology population given the potency of chronic inflammation on tumor development and progression. Second, HIIT may be an ideal strategy to employ for surgical prehabilitation [29, 34] where maximizing an exercise dose in a short waiting period is essential to achieve peri- and postoperative benefits while potentially controlling disease progression. Third, given potential safety concerns, more research is needed to conclusively determine adverse event rates and risk stratification when employing HIIT in people with cancer.