Lifestyle Factors and Cancer: A Narrative Review.

Article Highlights

Lifestyle modification has a beneficial impact on cancer outcomes.

Specific diet and physical activity patterns and their clinical impact are highlighted in this narrative review.

Mechanisms of oncogenesis in obesity and their modulation by lifestyle modification are described.

Summary tables of the largest randomized controlled trials and prospective studies of lifestyle modification are provided, enabling quick clinician reference to inform future discussions with patients.

The term lifestyle medicine is the study of how modifiable factors can impact health outcomes, including diet, physical activity, stress, social support, sleep, and mind-body connection, among others. Experts estimate at least 42% of newly diagnosed cancer cases in the United States are caused by modifiable lifestyle factors and are, therefore, potentially preventable. 1 Today, there is a large volume of data published on some modifiable risk factors, but there are still large gaps in our knowledge. Of these, primary lifestyle factors, specified here as dietary habits and physical activity, have the most evidence demonstrating an impact on cancer outcomes. 2 , 3 There are several measures/indices of the status of these 2 primary lifestyle factors, including weight, body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared), and obesity. Regardless of how diet and phsycial activity are measured, they have been associated with the risk of developing lung, prostate, colorectal, breast, mouth, throat, esophagus, pancreas, stomach, liver, and kidney cancers. 4 , 5 , 6 , 7 However, current research has focused mostly on breast and colorectal cancer subtypes.

Diet and physical activity significantly influence obesity, all have been linked with an increased risk in 13 cancers, many of which overlap the previous list. 8 Specifically, in the past 20 years, in the United States, excess weight (a surrogate for obesity) has been attributed to 14% and 20% of all cancer-related deaths in men and women, respectively. 9 Additionally, these primary lifestyle factors affect not only cancer incidence but also treatment outcomes, quality of life (QOL), and survivorship after the diagnosis. However, there is a paucity of larger randomized controlled trials (RCTs) investigating the effects of specific lifestyle interventions on the prevention, treatment, and recurrence of cancer.

In this narrative review, we first discuss the oncogenic mechanisms behind primary lifestyle factors (diet, physical activity, and, within these 2, obesity), followed by a discussion on the impact of adherance to lifestyle guidelines and dietary patterns on cancer incidence, based on primary data. Owing to the plethora of published literature, we describe the role of physical activity on cancer incidence using summative systematic reviews. Finally, we synthesize primary data on lifestyle factors in the survivorship setting and conclude with potential future directions.

Oncogenic Mechanisms Behind Lifestyle Factors

Carcinoigenesis is a complex process with multiple initiating events,which can be summarized by endogenous, exogenous, and environmental components ( Figure ). Lifestyle factors are part of the exogenous components, which include dietary patterns, physical activity, tobacco, and alcohol intake. 10 , 11 When combined with endogenous (genetic sequence variations, metabolic, and hormonal) and environmental (radiation, stress, infection, and toxins) factors, these insults induce sequence variations at the cellular level, leading to dysregulation of normal cellular process 12 and, ultimately, invasive cancer formation.

Obesity is a closely related measure of diet and physical activity (in addition to some endogenous components such as genetics, which are out of the scope of this review). Obesity has a significant role in cancer development, which may be modifiable by lifestyle factor changes. Obesity is characterized as a chronic inflammatory state, with elevated levels of proinflammatory cytokines and changes in adipokine secretion. This leads to oversecretion of insulin, culminating in increased release of insulin-like growth factor 1. 12 Both insulin and insulin-like growth factor 1 suppress apoptosis but promote cellular proliferation, angiogenesis, and lymphangiogenesis. 13 Many cancers express elevated levels of the insulin receptor, which are suspected to play a role in their oncogenesis. 14 Moreover, hyperinsulinemia stimulates metabolic pathways, resulting in elevated levels of reactive oxygen species that are known to induce DNA damage and may further contribute to carcinogenesis. 15 From a clinical standpoint, a higher dietary glycemic load/carbohydrate intake in individuals with BMI of ≥25kg/m 2 has been proposed to influence cancer growth by means of providing a constant supply of glucose for aerobic metabolism. 16

In an obese state, excess adipose tissue causes higher levels of endogenous sex hormones, as fat cells are where the enzymatic conversion of steroid precursors to hormones occurs. A clincial example is as in endometrial and breast cancer, where higher levels of circulating sex hormones have been implicated with increased risk of endometrial cancer and breast cancer in postmenopausal women. 17 , 18 Normally, adipose tissue releases a balance of adipokines (both proinflammatory and anti-inflammatory hormones and cytokines). In visceral obesity, however, anti-inflammatory hormones are secreted in relatively lower levels, disrupting the balance of proinflammation and anti-inflammation and, therefore, suspected to promote more tumorigenesis. 19 In addition, chronically low levels of anti-inflammatory products in obesity also promotes angiogenesis, a well-known tumor-associated vascular factor, critical for cancer propogation and survival. 20 , 21

Although obesity, which is related to more sedetary behavior, promotes carcinogenesis through the abovementioned mechanisms, physical activity has been found to promote adaptations in cells that might counter some oncogenesis aforementioned effects. Mechanistically, physical activity leads to short-term increases in the stress hormones norepinephrine and epinephrine but, overall, attenuates the body’s hormone responses to stress. 22 Physical activity also leads to the production of both proinflammatroy and anti-inflammatory cytokines but, specifically, interleukin-6, which leads to a cascade of overall anti-inflammatory cytokines and inhibits proinflammatory cytokines. Thereby, physcial activity may offer protection against chronic inflammation, such as that found in an obese state, which leads to oncogenesis. 23

The mechanisms described support the link among diet, physical activity, measured here by obesity, and cancer. Subsequently, potential modulation with physical activity provides an opportunity where lifestyle modification may mitigate the occurance of cancer. In summary, lifstyle factor modification with diet and physical activity patterns that lead to a healthy/nonobese state may offer a safe and effect management strategy to impact multiple protumorigeneic mechanisms, such as decreasing inflammation, enhancing the immune response, optimizing DNA repair and stability, and modulating hormonal responses.

Impact of Lifestyle Pattern Adherance on Cancer Incidence

Some authorities identify cancer as a chronic metabolic disease, with prevention strategies geared toward lifestyle factors that may influence other diseases related to cancer, including diabetes, obesity, hypertension, hyperlipidemia, and heart disease. 10 , 24 Interestingly, most of these comorbidities have a dysmetabolic state with overlaps with cancer mechanisms. In 2007, the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) promoted recommendations related to diet, nutrition, physical activity, and body composition in an effort to reduce incidence of cancer. 25

Among many studies investigating the association between adherence to these recommendations and cancer incidence, the VITAL study followed a large prospective cohort of 30,000 postmenopausal women and reported that adherence to ≥5 recommendations led to a 60% reduction in incidence of breast cancer. 26 Similarly, 2 other studies investigating adherence to WCRF/AICR recommendations reported a 51% and 24% reduction in breast cancer risk in postmenopausal women adhering to ≥6 of these guidelines. 27 , 28

In 2018, the Third Expert Report from the WCRF/AICR was published, highlighting the latest in cancer research and again emphasizing the interplay between diet and physical activity and the reduction in cancer rates. 29 Such findings suggest that the risk of many site-specific cancers can be reduced with implementation of WCRF/AICR recommendations. However, we note that there is a difference in quality of extrapobility between observational data included in the Third Expert Report and prospective studies such as the VITAL study, in which we can better assign a temporal relationship with adherance to recommendations and cancer outcomes.

Impact of Dietary Patterns on Cancer Incidence

Dietary interventions have reported a substantial impact on cancer development and prognosis. In this review, we focused on reviewing the largest prospective cohort studies (as RCTs have been limited), which heavily studied plant-based diets ( Table 1 ). However, we discuss these studies briefly but first narrate our current understanding of different diets and their theorized effects on cancer incidence, to understand why and how certain diets were chosen to be the focus of these large prospective trials. Non–plant-based diet of interest, including ketogenic and fasting intervals, are currently being explored in preclinical settings and small-scale clinical studies 30 with interesting but immature results. Of note, other specific diets such as ketogenic and fasting intervals are much more restrictive, difficult to comply with, and most importantly, have complex interactions that are cancer site-specific and, therefore, should not be broadly recommended. For example, ketosis can slow glioblastoma tumor formation because gliomas are unable to effectively use ketones, and this induces a direct Warburg effect. 31 However, epithelial cancer cells of the head and neck metabolize ketones and lactate efficiently, and some research shows that a ketogenic state might propagate the growth of these cancers. 32 Ketone bodies may be usable by the actively growing and stem cell–like component of tumors such as breast cancer 33 ; therefore, we need to better understand the long-term effects of a ketotic state in cancer. 34 A recent expert statement explained that most of the current published data support a plant-based diet over ketogenic diet as a safer and easier to maintain lifestyle to reduce cancer risk. 35

An understanding of the link between nutrition and cancer has led to the development of diets for both cancer prevention and treatment, including the whole-food plant-based diet (WFPBD). This dietary pattern is high in fiber, carotenoids, and polyphenols, while minimizing processed foods and animal products. Although the mechanisms underlying diet and cancer are complex, the WFPBD is suspected to lead to reductions in cancer incidence and all-cause mortality through reduction in BMI and sufficient intake of fiber, phytonutrients, and antioxidants. 36 In addition, as seen in the Adventist Health Study-2 and EPIC Oxford and Oxford Vegetarian Cohort, plant-based diets are linked with a reduction in cancer incidence. 37 , 38

In the Adventist Health Study-2, the association between various dietary patterns among 69,120 individuals was examined for overall incidence of any type of cancer except nonmelanoma skin cancer. When compared with nonvegetarian diet, plant-based diets were associated with a reduction in overall cancer risk with multivariate hazard ratio (HR) of 0.84 (95% CI, 0.72-0.99). 37 The WFPBD is highly rich in dietary fibers, which are associated with reductions in cancer-related mortality and all-cause mortality.

In addition high in fiber, the WFPBD is high in polyphenolic compounds, or flavonoids, which have been associated with health benefits. In a prospective study of 56,048 individuals, a moderate habitual intake of flavonoids was associated with lower risk of all-cause mortality. 39 Although robust randomized studies incorporating WFPBD are limited, data suggest this dietary pattern may be beneficial to patient outcomes.

These findings support the integration of dietary changes to decrease the incidence of cancer. There are several studies on different aspects of diet modification in cancer subtypes, but the differences in intervention type and tumor subtypes confound the ability to make general dietary recommendations across cancer types in the primary prevention setting. Assumedly, a patient would be interested in general prevention of all subtypes of cancer put together in a cohesive guideline, which is an area for future endeavors.

Role of Physical Activity in Cancer Incidence

There is a large body of literature revealing the impacts of physical activity and both cancer-related and all-cause mortality ( Table 2 ). In this review, we describe the impact of exercise in cancer prevention based on select systematic reviews. In a comprehensive review by Friedenreich et al, 40 the impact of physical activity and breast cancer was examined by looking at 34 case-control and 28 cohort studies. This review found that 30 of 62 studies reported that compared with less physically active women within their study populations, there was a significant risk reduction in the development of breast cancer among more physically activity women, with average risk reduction of 25%-30%. Higher reduction rates were seen among women engaging in recreational activity, vigorous intensity activity, and those who had performed physical activity throughout their lifetime compared with distinct ages in life.

Similar findings were found in the meta-analysis by Wolin et al 41 evaluating the association between physical activity and prevention of colon cancer. In their analysis, 52 studies when looking at 26 distinct cancer types in a pooled analysis from 12 prospective studies involving 1.44 million individuals, the overall relative risk of colon cancer was reduced for both men and women at 0.76 (95% CI, 0.71-0.82) and 0.79 (95% CI, 0.71-0.88), respectively. Moore et al 42 found that when compared with lower levels of leisure-time physical activity (10th percentile), there was a reduced risk of 13 cancer types among those engaging in higher levels of leisure-time physical activity (90th percentile) with risk reductions of ≥20% for 7 cancers.

These findings support the concept that regular recreational exercise is associated with significant cancer risk reduction. Similar to dietary patterns, differences in intervention design and tumor types make general physical activity recommendations difficult in cancer care as a whole, but relatively more physical activity than less is supported as a modifiable risk factor.

Impact of Obesity on Cancer Outcomes

As mentioned previously, obesity is closely related to diet and physical activity but does have some other endogenous/exogenous components. Because of this overlap, but of respect of the fact that obesity is a complex state not just equivalent to the sum of primary lifestyle factors, in this review, we mention some studies that looked at cancer outcomes stratified by obesity, not specifically diet or physical activity. Obesity has been attributed to an increased risk in both the development of and death from cancer. 9 Thus, it represents a modifiable risk factor that is commonly described in the literature. For example, obesity is implicated in studies evaluating weight loss (and, thus, reduced level of overweight/obesity) and BMI (which is a direct measure defining obesity) ( Table 1 ). However, the specific mechanisms by which obesity impacts cancer development, disease progression, and cancer-associated outcomes is just now starting to be understood. One such example is found in multiple myeloma (MM), which is preceded by a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS). This premalignant state is characterized by a spike in immunoglobulin in serum or urine without evidence of end-organ damage related to MM or other lymphoproliferative disorder. 43 , 44

Obesity represents the only known modifiable risk factor for MM, and therefore, studies have examined if there is an association between obesity and transformation of MGUS with MM. Although several studies have not found a direct association between obesity and MGUS, there does appear to be an associated risk in earlier transformation from MGUS to MM in obese individuals. 45 In 2 pivotal studies, obesity was associated with a younger age at time of transformation from MGUS to MM. 45 , 46 The exact mechanisms driving this are not well known although hypothesized to be related to concomitant comorbid conditions.

Impact of Lifestyle Factors on Survivorship Outcomes

In the survivorship after cancer, the most common malignancy studied is breast followed by colorectal cancer. Comparedwithother malignancies, there is a plethora of studies in patients with breast cancer, being the most commonly studied malignancy in the survivorship setting. Within physical activity, RCTs were mostly educational or physical intervention based and results all trended to significance. RCTs in physical activity in breast cancer reported improved overall survival and weight loss but were inconsistent in QOL and improved understanding of healthy lifestyle ( Table 2 ). 47 , 48 , 49 , 50 , 51 RCTs in dietary interventions in breast cancer found differences in risk of death and weight loss but not in breast cancer–related events. 49 , 52 , 53 Prospective studies in physical activity and breast cancer reported decreased risks of death especially in hormone-responsive breast cancer. 48 , 54 , 55 , 56 However, reduced risk of recurrence was not clearly found 57 ( Table 3 ).

There were more prospective studies in diet and breast cancer than physical activity. In general, a healthier diet, such as following the American Cancer Society guidelines, reduced (mostly saturated or animal) fat intake, plant-based diet, diabetes reduction, anti-inflammatory, and Mediterrainean diet (among others) was mostly associated with reduction risk of recurrence or death, with few exceptions that reported no difference ( Table 3 ). 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67

The second most commonly studied cancer is surviorship was colorectal cancer. There were mostly prospective trials on physical activity after colon cancer, and these studies found improved disease-related survivial for more active suriviors regardless of priagnostic activity. 68 , 69 , 70 , 71 , 72 One RCT found no significant differences between group for functional assessment changes before and after exercise intervention. 73 Studies of diet in survivors with colorectal cancer disfavored a western dietary pattern because it was associated with worse disease-free and overall survival and poor diet quality of processed foods and high sugar intake. 74 , 75 Instead, a higher American Cancer Society nutrition score, lower dietary hyperinsulinemia index, anti-inflammatory diet, and the Mediterranean diet were associated with positive outcomes, including lower risk of mortality, sometimes from colorectal cancer–specific mortality or other disease-related surivival. 72 , 76 , 77

Moving forward, studies combining physical activity and diet interventions or obstervations will likely show promise as lifestyle changes are multifactorial, and we cannot out-eat poor activity or out-exercise poor diet. Although, theoretically, we have some idea as to the biochemical mechanisms behind diet and activity, further research might also focus on understanding how diet andphysical activity biochemically change mortality outcomes. In general, more RCTs and prospective studies are needed in less common cancers, but some of these are underway. Ultimately, studies that combine qualitative QOL outcomes and more numerical oncologic outcomes such as recurrence risk/mortality might help us understand the “bigger picture” of the effect of diet and exercise on cancer survivorship.

Discussion

This narrative review emphasizes the importance of lifestyle on cancer prevention, prognosis, and survivorship. Although lifestyle factors do not independently influence cancer development, they are exogenous components that can modulate the underlying mechanisms that drive oncogenesis and, thereby, likely play a critical role in primary cancer risk and health outcomes after diagnosis. The studies presented in this review indicate that a signficant reduction in cancer incidence and all-cause mortality can be achieved through modification of diet and physical activity. It should be recognized we use the term lifestyle broadly in this review, given the diverse variation of interventions; hence, each intervention (ie, specific dietary and physical activity modifications) and associated cancer outcome should be critically reviewed for relevance in particular patient populations.

ALthough the role of healthy lifestyle on prevention and prognosis in cancer patients is generally well-established, the impact of lifestyle modifications on cancer survivorship is less elucidated. This review focused on the impact of lifestyle factors on survivorship in patients with breast and colorectal cancer because research in other malignancies is limited. Within the breast and colorectal cancer realm, the literature does show a trend toward improved disease-related survival and overall survival in patients adhering to WCRF/AICR guidelines. Such findings may be similar across other cancer types; however, more RCTs and prospective studies are needed to further clarify this. Moreover, some smaller studies have shown no beneficial effect of certain lifestyle interventions on cancer recurrence and QOL. Future research would benefit from larger cohort studies with longer follow-up times to ascertain the role of lifestyle modification on cancer survivorship.

Cancer development is associated with dysregulatory mechanisms of normal cellular processes, driven by both endogenous and environmental factors. Recent data have shown the contribution of obesity on oncogenesis through alterations in various pathways, culiminating in a state of chronic inflammation that leads to ongoing oxidative stress, proinflammatory cytokine and akipokine release, insulin resistance, and alterations in cellular microenviornment. 78 An understanding of obesity-related oncogenesis is therefore critical because we aim to reverse these dysfunctinal pathways through lifestyle modifications such as physical activity, weight loss, and dietary modifications.

Many studies to date have systematically reviewed the relationship of individual lifestyle factors on both incidence and all-cause mortality of cancer, giving us invaluable information to encourage patients to lead healthy lifestyles. Despite this, the volume of information can be overwhelming for clinicians to access, summarize, and apply in clinical practice. This narrative review provides clinicians a resource of the largest known studies to date, thus enabling evidence-informed counseling on diet and physical activity, with site-specific interventions.

There is limited research available investigating the impact of combined lifestyle intervention, which we identify as a potential area of future research. Although our review supports the impact of single lifestyle modifications on risk reduction in cancer incidence, more research is needed to identify the effects of multiple lifestyle interventions, applied simulataneous or sequentially, to investigate synergistic effects of the applied interventions. This includes stress and social support, that is, the mind-body connection, which has been implicated in the development of cancer incidences and progress. There is currently limited understanding of the impact of these 2 factors on the full reach of their impact on biological effects. To fill these gap, we need robust systems–based designed RCTs evaluating the effects of comprehensive lifestyle modifications on cancer prevention and prognosis. It would require patients to be followed up over decades, randomized to their “regular” lifestyle versus intervention with diets and physical activity, social support and stress interventions that are broadly feasible, implementable, and disseminable. Indeed, this would be an arduous but an impactful endeavor.

In summary, this narrative review highlights the potent clinical impact of lifestyle modification (specifically diet and physical activity) on cancer outcomes and reviews the oncogenic mechanisms modulated by lifestyle medicine, as both endogenous and exogenous factors. Although plenty of primary data exist, they are limited to cancer subtype, breadth and uniformity of interventions, and high-quality holistic interventions incorportating multimodal approaches (such as including stress modification in addition to diet and activity). This makes global and detailed recommendations difficult to acertain for the practicing clinician. This narrative review helps to summarize the key studies in the field of lifestyle medicine as they specifically relate to cancer, which can guide clinical practive recommendations and future research design.

Potential Competing Interests

The authors declare no conflicts of interest.

Footnotes

Grant support: None

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