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Challenges in the Clinical Treatment of Obese Cancer Patients Anahita Kodali '23
BY ANAHITA KODALI ’23
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Cover image: This graph represents the percentage of the population that was obese in OECD countries (an intergovernmental economic organization with 38 countries in its membership) plus the Czech Republic, Hungary, Mexico, Poland, and Slovakia as of 2005. Even 15 years ago, America had a significantly higher rate of obesity than the rest of the nations. This difference has persisted over time. Image Source: Wikimedia Commons Introduction
Cancer is one of the leading causes of death in the US and presents significant challenges to the healthcare systems of every country. In the US alone, there were about 1,806,590 new cancer cases in 2015 (“Cancer Statistics—National Cancer Institute,” 2015). In 2021, projected estimates for America have slightly increased – there will likely be about 1,898,160 new cancer cases (Siegel et al., 2021). Though the mortality of cancer in the US has decreased in the past 30 years due to advances in clinical and preventative medicine, its prevalence is on the rise and will probably continue to increase over the next several years (Weir et al., 2015).
The increase in cancer prevalence may be somewhat puzzling at first glance, given that there have been many advances made in medicine over the past few years and that many risk factors, such as smoking, are becoming less common (“WHO launches new report on global tobacco use trends,” 2019). However, several factors outweigh these positive changes. The first is population growth – as the population grows, more people are alive to be afflicted with disease. Additionally, the world’s population is aging. Between 1990 and 2019, the portion of the global population 65 years or older increased from 6% to 9%, and estimates suggest that by 2050, the proportion will have risen to 16% (United Nations et al., 2020). The risk of developing most cancers increases as people get older, though there are ways that people can modify their behaviors to decrease this likelihood (White et al., 2014). Finally, while the prevalence of many risk factors is decreasing, the prevalence of others is increasing; this includes obesity.
Obesity refers to the condition in which patients have accumulated abnormally excessive amounts of fat in their adipose tissue. The fat distribution can be varied – some patients have abdominal obesity, in which there is significant fat accumulation in the waist and torso, while others have gynoid obesity, in which there is significant fat accumulation peripherally around the body. There are several health consequences of obesity (regardless of type). For one, it increases the chance of type II diabetes, hypertension, coronary heart disease, stroke, disability, and premature mortality (Ofei, 2005). It also increases risk of several types of cancer: esophageal adenocarcinoma, meningioma,
Figure 1: Insulin, a hormone produced by the pancreas, has been implicated in pathways connecting obesity and cancer. Image Source: Flickr
multiple myeloma, and cancers of the breast, colon, gallbladder, kidney, liver, ovaries, pancreas, prostate, thyroid, and uterus; this idea is further explored in the following section (CDC Press Releases, 2016). It is no coincidence that many of these cancers are extremely common. Of the 19.3 million new cancer cases in 2020, breast cancer was the most commonly diagnosed, making up 11.7% of all diagnoses. Additionally, 10.0% were colorectal cancer, 7.3% were prostate cancer, and 5.6% were stomach cancer (Sung et al., 2021).
Worryingly, obesity rates are also on the rise. On a global scale, obesity has nearly tripled since 1975; as of 2016, more than 650 million adults were obese (“Obesity and overweight,” 2020). In the US, obesity is a particularly pressing problem. American obesity rates for adults have been rising since the 1980s; during the past decade alone, adult obesity rates grew from 33.7% to 39.6% (Hales et al., 2018). The rate of growth is not projected to slow in the coming years; some researchers estimate that by just 2030, nearly half of the American adult population will be obese, with the burden of disease falling heavily on women, Black adults, and low-income individuals (Ward et al., 2019).
Given the significant health effects of both cancer and obesity and their projected rises in the coming years, it has become increasingly important to understand the relationships between the two diseases. This paper aims to review the effects of obesity on cancer patients by looking at how obesity physically affects the body of cancer patients and impacts their treatment. The Biological Relationship Between Obesity and Cancer
As discussed previously, obesity increases the risk of several types of cancer. Though the correlation between the two is clear, researchers are still not completely sure how obesity leads to cancer. Since both cancer and obesity result from a wide range of physiological factors, the relationship between the two diseases has been particularly difficult to pinpoint. One such factor is sex – several obesityrelated cancers have sex-specific differences due to differences in hormonal levels. Race is another factor; for example, Black people have a significantly higher cancer risk in obesity as compared to Hispanic people, and Asian-Pacific populations have particularly high correlations between BMI and breast cancer (De Pergola & Silvestris, 2013). Given the complexities and variances in the relationship between the two diseases, it is clear that multiple biological mechanisms are at play. The three sources of interaction between cancer and obesity that have been well-studied and described in the literature are insulin and insulin-like growth factors (IGFs), sex hormones, and adipokines.
Insulin is a peptide hormone that is produced by the pancreas; it regulates metabolism by promoting absorption of glucose from blood into the liver, fat, and muscle cells. IGFs are growth factors involved in several processes, including glucose metabolism and cell proliferation, differentiation, and survival. The insulinIGF pathway is complex and involves several components, including insulin, IGF1, IGF2, six receptors, and seven IGF-binding proteins “Researchers have found that there is a direct correlation between the time since a person quit smoking and the benefits they reap from doing so."
Figure 2: Adipose tissue produces adipokines, many of which have been significantly linked to increasing the risk of certain cancers .
Image Source: Wikimedia Commons
(IGFBPs) (LeRoith et al., 2011; Basen-Engquist & Chang, 2013). The pathway is triggered in the hyperinsulinemic condition, or the condition in which there is a significantly higher than normal amount of insulin in the blood. Hyperinsulinemia has been linked to obesity and obesity-related complications (Lee et al., 2014). There are a couple of mechanisms accounting for this relationship, the main one being that obesity can lead to insulin resistance, which is a state in which fat and muscle and liver cells do not respond well to insulin, and subsequently hyperinsulinemia. This occurs because adipose tissue (which obese individuals have an excess of) releases a number of proteins, one of which is retinol-binding protein-4 (RBF4). An increase in RBF4 can induce insulin resistance by reducing activation of the phosphatidylinositol3-OH kinase signaling pathway. The result is twofold: for one, the under-activation promotes insulin resistance, which causes the pancreas to secrete excess insulin into the blood stream, inducing hyperinsulinemia. Secondly, since this pathway is critical in modulation of cell growth, differentiation, proliferation, motility, and survival, disruptions to its signaling can directly result in tumor growth. RBF4 also enhances expression of phosphoenolpyruvate carboxykinase, an enzyme in the liver that functions in gluconeogenesis (the metabolic generation of glucose from non-carbohydrate carbon substrates). Changes in both the insulin and gluconeogenesis processes can result in insulin resistance and therefore an increase in blood insulin levels (Kahn et al., 2006). Though it is still not completely understood exactly how hyperinsulinemia is linked to cancer, one leading hypothesis is that an increase of blood insulin leads to a decrease in IGFBPs. This, in turn, causes a change in the cell environment that promotes tumor growth. Additionally, the decrease in IGFBPs increases the amount of IGF1, which plays an important role in childhood growth and adulthood anabolism (the process of producing complex molecules from simpler ones). IGF1 increases have been associated with increased risk of certain cancers, including breast and prostate cancers; for older men, higher IGF1 levels also increase the risk of death from cancer. The mechanisms underlying IGF1’s relationship to cancer risk are still being explored (BasenEngquist & Chang, 2013).
Sex hormones, particularly estrogens, also play a role in linking obesity and cancer; the role of estrogens is especially significant for hormonedependent cancers (including breast, endometrial, ovarian, prostate, and uterine cancers). Increases in weight cause increases in the levels of circulating estrogen, which has several implications (De Pergola & Silvestris, 2013). When estrogens bind to estrogen receptors, they activate intracellular pathways that stimulate cell division. Estrogens also interact with IGFs to inhibit apoptosis; combined, these significantly increase the rate of tumor growth (Basen-Engquist & Chang, 2013). Finally, estrogens, along with free radicals (highly reactive and unstable molecular species), have been known to induce DNA damage, genetic instability, and gene mutations, all of which can induce and promote tumor growth (De Pergola & Silvestris, 2013).
Adipokines, or hormones produced by adipose tissue, are also a significant factor in cancer. Obesity results in an excess of adipose tissue
found throughout the body. Thus, in the obese condition, there is a significantly high number of adipokines in the blood (Zorena et al., 2020). Perhaps the most well-known adipokine is leptin, a hormone involved in energy balance regulation via hunger inhibition. There are several reasons for this: leptin inhibits apoptosis and promotes cell division, inflammation, and development of blood vessels, all of which work in tandem to cause tumor proliferation (De Pergola & Silvestris, 2013). The role of leptin has been extensively studied in breast cancer, though increased blood serum levels of leptin have also been associated with increased risk of colon and prostate cancers (De Pergola & Silvestris, 2013; Basen-Engquist & Chang, 2013). Leptin is particularly significant in the onset and growth of tumors in breast cancer because breast epithelial cells contain leptin receptors, and leptin increases estrogen production. Interestingly, adiponectin, the most abundant adipokine, plays a protective role against cancer; the greater circulating levels of adiponectin caused by obesity are inversely related to cancer risk. There are two main reasons for this. The first is that it enhances insulin sensitivity, lowering the effects of insulin resistance and hyperinsulinemia. Additionally, it activates the AMPK pathway, which regulates energy homeostasis by inducing glucose and fatty uptake by cells (De Pergola & Silvestris, 2013). The AMPK pathway inhibits virtually all of the anabolic pathways in the body that promote cell growth, so increased activation of the pathway through increased circulation of adiponectin reduces cancer growth (Li et al., 2015). These competing effects are complex and need to be studied in more detail to be better understood.
In addition to insulin, sex hormones, and adipokines, several other factors relate obesity to tumor growth. One is that obesity tends to generate chronic inflammation of adipose tissue. This results in excessive adipose tissue expansion, which in turn causes an increase in cancer-related adipocytes and adipose-derived stem cells. Both will enter the tumor microenvironment and execute protumor action (Deng et al., 2016). Additionally, obesity may reduce the body’s antioxidant activities (activities that limit the number of free radicals in the body), thus increasing oxidative stress, which may cause DNA damage that can increase cancer risk. In line with this genetic effect, there are certain genetic predispositions to obesity that may also predispose development of cancer (De Pergola & Silvestris, 2013). As more research is done on obesity and cancer, it is more than likely that more links between the two will be found. In addition to cancer initiation and growth, obesity is related to worsened quality of life for cancer patients and increased mortality risk. In a study done on breast cancer patients, obesity was related to worse tumor characteristics in obese individuals compared to normal-weight controls. Obese patients’ tumors were typically diagnosed at later stages, were larger, and were more likely to spread than those of normal-weight individuals; additionally, lymph nodes were more likely to contain cancer. In turn, obesity was related to a higher likelihood that the cancers were fatal, accounting for obesity-related risks of mortality (Blair et al., 2019). Though more studies need to be done on the direct impacts of obesity on other types of obesity-related cancers, obesity tends to elevate mortality rates for all comorbidities (Abdelaal et al., 2017).
The Effect of Obesity on the Therapeutic Approach
In addition to the relationship between obesity and the onset, progression, symptoms, and mortality rates of cancer, researchers are working to understand the role that obesity may play in the clinical treatment of cancer. Three common types of cancer treatment are surgery, radiation therapy, and chemotherapy; often, a combination of the three is used. For patients who undergo cancerremoval surgery, the data on the correlation between obesity and outcome is somewhat unclear. In terms of mortality and major complications, there seems to be no association with BMI. However, there is a significant increase in minor surgical complications correlated with an increase in BMI; these can include infection and wound dehiscence (wounds splitting open). Lymphedema, or excess fluid collection in tissues, is also a major issue after surgery for obese cancer patients, and issues with wounds and fluid buildup are due to a variety of reasons, including increased wound tension and tissue pressure and decreases in vascularity around adipose tissue. Though minor complications may not be as devastating as major complications, they can result in increased surgery time and increased blood loss, which can lead to longer recovery times, greater costs for patients, and delays in additional cancer treatments (like chemotherapy and radiation). Additionally, obese cancer patients have a higher risk of having surgical margins that are positive for cancer cells; in other words, when the doctors tries to cut away the cancer, they leave cancerous cells behind. This results in poorer outcomes and higher chances of cancer recurrence (Ross et al., 2019). “Obese patients’ tumors were typically diagnosed at later stages, were larger, and were more likely to spread than those of normalweight individuals; additionally, lymph nodes were more likely to contain cancer."
Figure 3: CT visualization of cancer can be complicated by obesity. Image Source: Flickr Patient obesity also impacts radiation therapy practice. For one, it can be difficult to properly image an obese patient in the computed tomography (CT) scanner before the radiation is applied; CT scans are necessary to visualize the cancer so that the radiation beams can be aligned correctly. Once the cancer has been visualized, it can be difficult to precisely target radiation beams on obese patients, both because tattooing the patient (to properly line up the beams) can be challenging and because moving the patient into the proper position in the radiation therapy treatment unit is difficult (Winters & Poole, 2020). These issues can all lead to inferior treatment outcomes and reduce the efficacy of treatment (Ross et al., 2019). Furthermore, for patients with certain cancers, including cervical and endometrial, obesity may increase radiotherapyinduced toxicity posttreatment through mechanisms still being explored. Radiotherapyinduced toxicity cause adverse effects in patients (Ross et al., 2019; Dandapani et al., 2015). Some of these effects are short-term, like inflammation of the gut and mouth, while longer term effects, including fibrosis, are largely irreversible (De can have a significant impact on the efficacy of chemotherapy. Patient dosing is calculated using body surface area (BSA) in adult patients. It is critically important that all patients receive a dosage based on their BSA; however, up to 40% of obese patients may receive a smaller dosage that is based on a doctor’s calculation using an arbitrarily capped BSA in order to reduce chemotherapy-related toxicity, as the decision up to the doctor’s own judgement (Ross et al., 2019). This reduction in dosing is correlated with reduced overall survival (OS) and progressionfree survival (PFS); indeed, in studies done with gynecological cancer patients, properly dosing patients using their BSA found that there was no difference in OS or PFS between obese and nonobese patients for most chemotherapy drugs, demonstrating that proper dosage intensity for obese patients improves outcomes (Ross et al., 2019; Horowitz & Wright, 2015).
This brings up an important issue: patient-doctor relations. Researchers have found that generally, doctors build lower levels of emotional rapport with overweight and obese patients. This results
Ruysscher et al., 2019).
Obese patients who undergo chemotherapy typically have worse outcomes than non-obese patients. The main reason for this may be issues in properly dosing patients. Obese patients can have issues with metabolic regulation and with pharmacokinetics (the movement of drugs throughout the body), which can lower the efficacy of chemotherapy (Horowitz & Wright, 2015). Perhaps more significantly, doctors’ choices in how to dose obese patients in weaker patient-doctor relationships, which in turn can make patients less likely to adhere to medication plans and can decrease the effectiveness of behavior modification therapies (Gudzune et al., 2013). There is a consensus among medical staff that obese cancer patients may be unintentionally treated with a lack of dignity. For example, radiotherapy technicians have reported that patients seem to be conscious and apologetic of their bodies while undergoing imaging; they also report feeling frustrated with obese patients, even on first visits, due to the difficulty of treating
obese cancer patients (Winters & Poole, 2020). Thus, moving forward, it is important for medical staff treating obese patients to be mindful of not just the therapeutic challenges that obesity can cause in cancer treatment but of their demeanor towards cancer patients. The patient-doctor relationship in particular is especially powerful in patient outcomes – more positive patient-doctor relationships lead to greater patient satisfaction, better patient understanding of their disease, and higher patient compliance with treatment (“The Importance of Physician-Patient Relationships,” 2019). Each of these factors may improve the efficacy of cancer treatment and may lead to better OS and PFS in obese cancer patients.
As discussed previously, obesity is caused by (and causes) dysregulation of several bodily processes, many of which are still not entirely understood. One of the most widely studied theories has been set-point theory, which argues that the body’s natural weight is maintained in a stable range called the set-point through various homeostatic mechanisms and feedback loops; the set-point is thought to be strongly influenced by genetics (Müller et al., 2018). Especially important is that the body seems to be much more efficient at preventing weight loss than weight gain (Farias et al., 2011). This model explains why many obese patients are resistant to weight loss just by caloric restriction. As such, many treatments for obesity try to influence the body’s natural weight set-point in order to allow the patient to lose weight sustainably. However, for obese cancer patients, treatment focuses on both cancer and obesity. Interventions for obesity during and after cancer treatment are complicated, as doctors need to make sure that they are not exacerbating the patient’s cancerrelated symptoms. There are several areas of intervention for obese patients. Perhaps the most well studied currently are dietary interventions, which are critical to managing the weight of all obese patients; it becomes particularly important in the context of cancer treatment because cancer patients require nutritional management to avoid excessive weight loss. Adequate nutrition for all cancer patients – both normal-weight and obese – maximizes efficacy of treatment and reduces negative side effects. Generally, nutrition is not well managed for cancer patients, further emphasizing the special attention needed for obese cancer patients (Ravasco, 2019). During cancer treatment, weight loss of obese patients is associated with malnutrition; thus, it is critical to maintain lean mass while in treatment so in order to preserve patient functionality and quality of life, both of which may mitigate the side effects of cancer treatment. Diets should lower “empty” calories (calories from saturated fats and refined sugars) and emphasize protein from dairy, fish, eggs, meat, and legumes. After treatment, dietary intervention is still critical, especially because patients are at higher risk for obesity after recovering from one illness (Pérez-Segura et al., 2017).
Less research has been done on other interventions. One important area may be physical activity. It is known that regular physical activity has a protective effect against several types of cancer (Schrack et al., 2017). Additionally, after cancer treatment, regular exercise can help alleviate several physical and mental health issues, including fatigue, anxiety, and depression (Schmitz et al., 2019). For obese cancer patients especially, regular physical activity during and after treatment can lower recurrence of certain cancer and increase survivability; additionally, it can increase muscle mass and strength, lower fat, and improve self-esteem. As such, emphasizing the importance of physical activity for obese cancer patients may significantly improve outcomes, and in the coming years, it is likely that doctors will place greater significance on regular exercise as a part of cancer treatment for all cancer patients. Additionally, bariatric surgery after cancer treatment is a viable option for many cancer patients once the patient is cancer free. Finally, providing strong therapeutic support for obese cancer patients can improve patients emotional and physical states and improve quality of life both during and after treatment (Pérez-Segura et al., 2017).
Conclusions
Cancer treatment is difficult in the best of circumstances. For obese cancer patients, treatment can be variable; as such, the patients require special care and attention from medical staff. As the current rate of obesity, both in the US and around the world, continues to grow, it is likely that the number of obese cancer patients will rise, too. Thus, it is important for doctors to learn how to effectively treat obese cancer patients and to develop interventions for obesity both during and after treatment. As treatment plans and interventions are better researched, patient outcomes for obese cancer patients will hopefully improve.
References
Abdelaal, M., le Roux, C. W., & Docherty, N. G. (2017). Morbidity and mortality associated with obesity. Annals of "more positive patientdoctor relationships lead to greater patient satisfaction, better patient understanding of their disease, and higher patient compliance with treatment"
Translational Medicine, 5(7), 161–161. https://doi.org/10.21037/ atm.2017.03.107
Basen-Engquist, K., & Chang, M. (2011). Obesity and Cancer Risk: Recent Review and Evidence. Current Oncology Reports, 13(1), 71–76. https://doi.org/10.1007/s11912-010-0139-7
Blair, C. K., Wiggins, C. L., Nibbe, A. M., Storlie, C. B., Prossnitz, E. R., Royce, M., Lomo, L. C., & Hill, D. A. (2019). Obesity and survival among a cohort of breast cancer patients is partially mediated by tumor characteristics. Npj Breast Cancer, 5(1), 33. https://doi.org/10.1038/s41523-019-0128-4
Broom, A., Kenny, K., Page, A., Cort, N., Lipp, E. S., Tan, A. C., Ashley, D. M., Walsh, K. M., & Khasraw, M. (2020). The Paradoxical Effects of COVID-19 on Cancer Care: Current Context and Potential Lasting Impacts. Clinical Cancer Research, 26(22), 5809–5813. https://doi.org/10.1158/10780432.CCR-20-2989
Cancer Statistics—National Cancer Institute (nciglobal,ncienterprise). (2015, April 2). [CgvArticle]. https:// www.cancer.gov/about-cancer/understanding/statistics
CDC Press Releases. (2016, January 1). CDC. https://www.cdc. gov/media/releases/2017/p1003-vs-cancer-obesity.html
Dandapani, S. V., Zhang, Y., Jennelle, R., & Lin, Y. G. (2015). Radiation-Associated Toxicities in Obese Women with Endometrial Cancer: More Than Just BMI? The Scientific World Journal, 2015, 1–6. https://doi.org/10.1155/2015/483208
De Pergola, G., & Silvestris, F. (2013). Obesity as a Major Risk Factor for Cancer. Journal of Obesity, 2013. https://doi. org/10.1155/2013/291546
De Ruysscher, D., Niedermann, G., Burnet, N. G., Siva, S., Lee, A. W. M., & Hegi-Johnson, F. (2019). Radiotherapy toxicity. Nature Reviews Disease Primers, 5(1), 13. https://doi. org/10.1038/s41572-019-0064-5
Deng, T., Lyon, C. J., Bergin, S., Caligiuri, M. A., & Hsueh, W. A. (2016). Obesity, Inflammation, and Cancer. Annual Review of Pathology: Mechanisms of Disease, 11(1), 421–449. https://doi. org/10.1146/annurev-pathol-012615-044359
Farias, M. M., Cuevas, A. M., & Rodriguez, F. (2011). SetPoint Theory and Obesity. Metabolic Syndrome and Related Disorders, 9(2), 85–89. https://doi.org/10.1089/met.2010.0090
Gudzune, K. A., Beach, M. C., Roter, D. L., & Cooper, L. A. (2013). Physicians build less rapport with obese patients: Rapport Building Obesity. Obesity, 21(10), 2146–2152. https:// doi.org/10.1002/oby.20384
Hales, C. M., Fryar, C. D., Carroll, M. D., Freedman, D. S., & Ogden, C. L. (2018). Trends in Obesity and Severe Obesity Prevalence in US Youth and Adults by Sex and Age, 2007-2008 to 2015-2016. JAMA, 319(16), 1723. https://doi.org/10.1001/ jama.2018.3060
Horowitz, N. S., & Wright, A. A. (2015). Impact of obesity on chemotherapy management and outcomes in women with gynecologic malignancies. Gynecologic Oncology, 138(1), 201–206. https://doi.org/10.1016/j.ygyno.2015.04.002
Kahn, S. E., Hull, R. L., & Utzschneider, K. M. (2006). Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature, 444(7121), 840–846. https://doi.org/10.1038/ nature05482 Lee, Y., Berglund, E. D., Yu, X., Wang, M.-Y., Evans, M. R., Scherer, P. E., Holland, W. L., Charron, M. J., Roth, M. G., & Unger, R. H. (2014). Hyperglycemia in rodent models of type 2 diabetes requires insulin-resistant alpha cells. Proceedings of the National Academy of Sciences, 111(36), 13217–13222. https:// doi.org/10.1073/pnas.1409638111
LeRoith, D., Scheinman, E. J., & Bitton-Worms, K. (2011). The Role of Insulin and Insulin-like Growth Factors in the Increased Risk of Cancer in Diabetes. Rambam Maimonides Medical Journal, 2(2). https://doi.org/10.5041/RMMJ.10043
Li, W., Saud, S. M., Young, M. R., Chen, G., & Hua, B. (2015). Targeting AMPK for cancer prevention and treatment. Oncotarget, 6(10), 7365–7378. https://doi.org/10.18632/ oncotarget.3629
Müller, M. J., Geisler, C., Heymsfield, S. B., & Bosy-Westphal, A. (2018). Recent advances in understanding body weight homeostasis in humans. F1000Research, 7, 1025. https://doi. org/10.12688/f1000research.14151.1
Obesity and overweight. (n.d.). Retrieved March 26, 2021, from https://www.who.int/news-room/fact-sheets/detail/obesity-andoverweight
Ofei, F. (2005). Obesity—A Preventable Disease. Ghana Medical Journal, 39(3), 98–101.
Pérez-Segura, P., Palacio, J. E., Vázquez, L., Monereo, S., de las Peñas, R., de Icaya, P. M., Grávalos, C., Lecube, A., Blasco, A., García-Almeida, J. M., Barneto, I., & Goday, A. (2017). Peculiarities of the obese patient with cancer: A national consensus statement by the Spanish Society for the Study of Obesity and the Spanish Society of Medical Oncology. Clinical and Translational Oncology, 19(6), 682–694. https://doi. org/10.1007/s12094-016-1601-2
Ravasco, P. (2019). Nutrition in Cancer Patients. Journal of Clinical Medicine, 8(8), 1211. https://doi.org/10.3390/ jcm8081211
Ross, K. H., Gogineni, K., Subhedar, P. D., Lin, J. Y., & McCullough, L. E. (2019). Obesity and cancer treatment efficacy: Existing challenges and opportunities. Cancer, 125(10), 1588–1592. https://doi.org/10.1002/cncr.31976
Schmitz, K. H., Campbell, A. M., Stuiver, M. M., Pinto, B. M., Schwartz, A. L., Morris, G. S., Ligibel, J. A., Cheville, A., Galvão, D. A., Alfano, C. M., Patel, A. V., Hue, T., Gerber, L. H., Sallis, R., Gusani, N. J., Stout, N. L., Chan, L., Flowers, F., Doyle, C., … Matthews, C. E. (2019). Exercise is medicine in oncology: Engaging clinicians to help patients move through cancer. CA: A Cancer Journal for Clinicians, 69(6), 468–484. https://doi. org/10.3322/caac.21579
Schrack, J. A., Gresham, G., & Wanigatunga, A. A. (2017). Understanding physical activity in cancer patients and survivors: New methodology, new challenges, and new opportunities. Molecular Case Studies, 3(4), a001933. https:// doi.org/10.1101/mcs.a001933
Siegel, R. L., Miller, K. D., Fuchs, H. E., & Jemal, A. (2021). Cancer Statistics, 2021. CA: A Cancer Journal for Clinicians, 71(1), 7–33. https://doi.org/10.3322/caac.21654
Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (n.d.). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, n/a(n/a). https://doi.org/10.3322/caac.21660
The Importance of Physician-Patient Relationships Communication and Trust in Health Care. (2019, March 11). Duke Personalized Health Care. https://dukepersonalizedhealth. org/2019/03/the-importance-of-physician-patient-relationshipscommunication-and-trust-in-health-care/
United Nations, Department of Economic and Social Affairs, & Population Division. (2020). World population ageing, 2019 highlights.
Ward, Z. J., Bleich, S. N., Cradock, A. L., Barrett, J. L., Giles, C. M., Flax, C., Long, M. W., & Gortmaker, S. L. (2019). Projected U.S. State-Level Prevalence of Adult Obesity and Severe Obesity. New England Journal of Medicine, 381(25), 2440–2450. https:// doi.org/10.1056/NEJMsa1909301
Weir, H. K., Thompson, T. D., Soman, A., Møller, B., & Leadbetter, S. (2015). The Past, Present, and Future of Cancer Incidence in the United States: 1975 Through 2020. Cancer, 121(11), 1827–1837. https://doi.org/10.1002/cncr.29258
White, M. C., Holman, D. M., Boehm, J. E., Peipins, L. A., Grossman, M., & Henley, S. J. (2014). Age and Cancer Risk. American Journal of Preventive Medicine, 46(3 0 1), S7-15. https://doi.org/10.1016/j.amepre.2013.10.029
WHO launches new report on global tobacco use trends. (n.d.). Retrieved March 24, 2021, from https://www.who.int/news/ item/19-12-2019-who-launches-new-report-on-global-tobaccouse-trends
Winters, E., & Poole, C. (2020). Challenges and impact of patient obesity in radiation therapy practice. Radiography, 26(3), e158–e163. https://doi.org/10.1016/j.radi.2020.01.005
Zorena, K., Jachimowicz-Duda, O., Ślęzak, D., Robakowska, M., & Mrugacz, M. (2020). Adipokines and Obesity. Potential Link to Metabolic Disorders and Chronic Complications. International Journal of Molecular Sciences, 21(10), 3570. https://doi.org/10.3390/ijms21103570