Marjorie Cypress, PhD, MSN, RN, C-ANP, CDE1
1Cypress is an adult nurse practitioner and certified diabetes educator in Albuquerque, NM.
Besides the well-known complications of diabetes, such as cardiovascular disease, retinopathy, nephropathy and neuropathy, certain cancers have been associated with diabetes. Over recent years, numerous epidemiological studies have noted the increased risk of cancer among those with diabetes, and even prediabetes.1 Although much of the literature is recent, Elliot Joslin recognized the need to study this association citing earlier work (1910) that had linked the two diseases.2 Evidence of an association between diabetes, particularly type 2 diabetes (T2D), and certain cancers, specifically liver, pancreatic, kidney, endometrial, colorectal, bladder, breast, and non-Hodgkin’s lymphoma, seems to be unequivocal, with relative risk ranging for developing cancer from 1.12 to 2.50 (see Table 32.1).3 The association is not totally understood, but it may result from shared risk factors between T2D and cancer and also may be due to diabetes-related factors, such as underlying disease physiology or diabetes treatments, although evidence for these links is scarce. The modifiable risk factors for diabetes in many instances mimic some of the risk factors for certain cancers, such as obesity, physical inactivity, unhealthy nutrition, smoking, and alcohol.3 Some patients can develop diabetes as a result of the type of cancer treatment. The challenges faced by patients with both diseases are compounded, and nurses have an opportunity to provide medical and lifestyle counseling and emotional support. The preventive strategies that nurses and other health-care professionals recommend for diabetes, also can be used in cancer prevention. This chapter will discuss some of the recent information on diabetes and cancer risk along with nursing implications.
Table 32.1—Relative Risks of Cancer in Different Organs of Diabetic Patients
|
Cancer |
RR (95% CI) |
|
|
Liver (El-Serag et al. 2006) |
13 case-control studies |
2.50 (1.8–3.5) |
|
Pancreas (Huxley et al. 2005) |
17 case-control studies |
1.94 (1.53–2.46) |
|
Kidneya (Lindblad et al. 1999, Washio et al. 2007) |
1 cohort study |
1.50 (1.30–1.70) |
|
Endometrium (Friberg et al. 2007) |
13 case-control studies |
2.22 (1.80–2.74) |
|
Colon-rectum (Larsson et al. 2005) |
6 case-control studies |
1.36 (1.23–1.50) |
|
Bladder (Larsson et al. 2006) |
7 case-control studies |
1.37 (1.04–1.80) |
|
Non-Hodgkin’s lymphoma (Mitri et al. 2008) |
5 cohort studies |
1.41 (1.07–1.88) |
|
Breast (Larsson et al. 2007) |
5 case-control studies |
1.18 (1.05–1.32) |
|
Prostate (Kasper & Giovannucci 2006) |
9 case-control studies |
0.89 (0.72–1.11) |
aData on kidney cancer were not obtained from meta-analysis.
Source: Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr Relat Cancer 2009;16(4):1103–1123. Reprinted with permission from the publisher.13
EPIDEMIOLOGY
With the prevalence of diabetes increasing, ~26.9% of all people >65 years old have diabetes.4 The incidence of diagnosed diabetes and undiagnosed T2D increases with age, from 4.1% of the population between 20 and 44 years old, to 16.2% between 45 and 64 years old, and to 25.9% for those ≥65 years of age.4 According to the American Cancer Society, 86% of all cancers are diagnosed in people ≥55 years of age.5
Overall 8–18% of cancer patients have diabetes.6 Prediabetes also has been associated with a 15% increased risk for cancer overall, highest for liver, endometrial, and stomach cancers.1 According to the National Cancer Institute, having diabetes was associated with an 11% increased risk of dying from cancer among women and a 17% increased risk of death from cancer among men.7 Overall, evidence suggests that 35% of people will have a diagnosis of diabetes in their lifetime, 44% a diagnosis of cancer, and 15% will have both diseases.7 Those with BMI >40 kg/m2 had a dramatic reduction in life expectancy and increased the risk of dying at a younger age from cancer.8 Numerous epidemiological studies suggest obesity and T2D are correlated positively with both risks of cancer and cancer-related mortality,9 and cancer patients with diabetes had higher mortality rates than cancer patients without diabetes.10–12
PATHOPHYSIOLOGY: THEORIES ON ASSOCIATION
Although the pathophysiology between diabetes and cancers is not understood, hyperinsulinemia and insulin resistance along with chronic inflammation may be contributing factors, although evidence is scarce. Insulin is a potent promoter of cell growth and thus hypothetically could spur the development of common cancers.13 Hyperinsulinemia can lead to metabolic dysfunction, and theoretically promote oncogenesis by a disruption of insulin signaling and increasing insulin growth factor 1 (IGF1). IGF1, involved in cell growth and proliferation, also may affect cell metabolism.9,14,15 The metabolic effects of obesity such as increased levels of IGF1 also may play a role in specific cancers in people with diabetes.16 Chronically elevated insulin levels and insulin resistance also may facilitate cell migration and enhanced tumor growth.16 In addition, adipose tissue, an active endocrine organ, produces free fatty acids, plasminogen activation inhibitor 1, adiponectin, leptin, and interleukin 6, all of which may play a role in cancer progression.17 Low-grade chronic inflammation, such as can be present in diabetes, decreases antioxidant capacity, leading to the formation of reactive oxygen species (ROS). Elevated rates of ROS can cause cell death and have been detected in almost all cancers, where they promote many aspects of tumor development and progression.17
Cancers Associated with Diabetes
Of the cancers linked to diabetes, both colorectal cancer (CRC) and breast cancer are obesity related. CRC shares risk factors of obesity, sedentary lifestyle, and high caloric diet. Peeters et al.18 found a 1.3-fold increase in CRC in patients treated for T2D, particularly in patients with ≥4 years of obesity. Other large prospective studies still showed an increase risk of CRC in people with diabetes even when accounting for BMI and physical inactivity.19Interestingly, certain experimental animal studies show that when an animal overeats, the cancers are more aggressive, but when the animal is calorie restricted, the cancer is less aggressive, although it is unclear whether these findings apply to humans.17 Obesity or overweight, physical inactivity, and high-calorie diets have been associated with increased risks of several cancers.20,21 T2D associated with high BMI is also a well-established risk factor for breast cancer in postmenopausal women and is associated with poor prognosis regardless of menopausal status. The risk of breast cancer is increased in obese postmenopausal women by ~50%, but it is marginally reduced in premenopausal obese women.22,23
Other cancers with increased prevalence in individuals with diabetes include liver, pancreatic, and endometrial cancers. People with diabetes already may have some of the chronic complications of diabetes when diagnosed with cancer. Elevated liver enzymes often seen in T2D may be related to fatty liver or nonalcoholic fatty liver disease (NAFLD) and are associated with the prevalence of primary liver cancer, the most common hepatocellular carcinoma (HCC). Although HCC is seen more frequently in individuals with alcoholism and hepatitis B and C, it is widely recognized that T2D and dyslipidemia confer increased risk when compared with those without diabetes.3,24 Despite some shared risk factors with T2D, HCC has been shown to independently influence cancer risk.6
Diabetes is a significant risk factor for pancreatic cancer.25 Approximately 80% of patients with pancreatic cancer have diabetes or glucose intolerance,3 and diabetes can be an early manifestation of pancreatic cancer.26 A systematic review and dose response meta-analysis of studies of individuals with pancreatic cancer showed a strong association between fasting blood glucose and rates of pancreatic cancer across prediabetes and diabetes. The authors of the review noted that every 10 mg/dL increase in fasting blood glucose was associated with a 14% increase in the rate of pancreatic cancer.26
A growing body of evidence indicates that diabetes is a risk factor for endometrial cancer. In the Women’s Health Initiative, the higher risk of endometrial cancer among women with T2D was not statistically significant after adjusting for BMI. The independent risk of developing endometrial cancer, however, was modestly elevated.27 Other analyses concluded that evidence of an independent association between diabetes and endometrial cancer is consistent.26,28
A word of caution when reviewing all of the cancer-related studies. Colmers et al.29 noted the potential for bias, as epidemiological evidence suggests an initial period of increased risk for most solid cancers in the month immediately following the diagnosis of diabetes, followed by a decline and a leveling off of risk after the first year. This suggests the potential of an early detection bias because individuals with newly diagnosed diabetes tend to be seen more frequently by their providers and are assessed more thoroughly. This may increase the chances of identifying a cancer earlier. Further research with well-controlled randomized trials concerning diabetes and cancer are necessary. It is prudent, however, to be aware of the association between diabetes and cancer.
Diabetes Medications Associated with Cancer
Several medications used to treat diabetes have been thought to increase or decrease the risk of cancer. Several authors have noted multiple methodological problems in the research specifically in regard to metformin use and a lower risk of cancer. Also, many studies are observational or retrospective.30,31 This, however, should not totally negate the findings of much of this literature, but it should warn us to keep a keen eye when evaluating the many studies. The most recent study comparing metformin to other diabetes medications did not find any evidence to support a lower incidence of cancer.30 Pioglitazone was believed to cause bladder cancer, but several studies have not found any statistically significant increase in the risk of bladder cancer.32–34 There appears to be a slight increase in bladder cancer with pioglitazone when compared to the general population, and it is important for the patient and health-care professional to weigh the treatment benefits versus risks, as well as assess other risk factors, such as smoking and family history. Although the risk is low, the association is stronger with a higher cumulative dose and increased duration of exposure to the drug.32,33 Any patient with T2D newly diagnosed with bladder cancer should discontinue taking pioglitazone.34
Glargine insulin was found to be safe without adverse outcomes in the Outcome Reduction with Initial Glargine Intervention (ORIGIN trial).35 In addition, a recent systematic review and meta-analysis did not find any compelling evidence that any clinically available insulin analog (aspart, determir, glargine, glulisine, or lispro) or human insulin increases breast cancer risk.36 Sulfonylureas and other insulin secretagogues have been implicated in an increased risk of cancer. Recently, a study with a large cohort of people with diabetes newly prescribed glyburide or other second-generation sulfonylureas did not show a statistically significant association with cancer, but a secondary analysis indicated that a longer cumulative duration and dose was associated with any cancer.37
Some evidence suggests that incretin mimetics, such as glucagon-like peptide-1 (GLP1) agonist and dipeptyl peptidase (DPP-4) inhibitor medications, may increase the risk for acute pancreatitis. Chronic pancreatitis is associated with an increased risk of pancreatic cancer. A concern regarding thyroid medullary cancer with the use of GLP1 receptor agonists was identified in rat models but has not been substantiated in observations of humans. A recent updated review on cancer risk associated with incretin mimetics stated the following:
“[W]ith regards to cancers other than pancreatic cancer and thyroid cancer, available studies supported a neutral association in humans. Some preliminary studies even suggested a potentially beneficial effect on the development of other cancers with the use of incretins. Based on current evidence, continuous monitoring of the cancer issues related to incretin-based therapies is required, even though the benefits may outweigh the potential cancer risk in the general patients with type 2 diabetes mellitus.38”
Another recent review focusing on liraglutide indicated that no clear and significant associations between liraglutide and pancreatitis or pancreas cancer seem evident.39 The authors of these reviews and others, however, advise remaining vigilant and continuing to monitor the safety of both GLP1 and DPP-4 inhibitors.38–41 Certainly, patients will have concerns about medications, and it is the obligation of nurses and other health-care professionals to be aware of side effects, adverse effects, and risks.
Cancer Treatment: Diabetes and Chemotherapeutic Agents
Patients with diabetes may present unique challenges to clinicians making cancer treatment decisions. Patients with longstanding diabetes or a history of poorly controlled diabetes may present for cancer treatment with preexisting renal, cardiac, or neuropathic complications. Several chemotherapeutic agents are known to cause or exacerbate these conditions. For example, cisplatin is known to cause renal insufficiency, and the anthracyclines may cause cardiotoxicity. Cisplatin, paclitaxel, and vincristine may be neurotoxic. Unfortunately, many of these side effects from chemotherapeutic agents are permanent.
Successful cancer treatment usually requires that at least 85% of the chemotherapeutic dose be given. Patients with diabetes must be monitored carefully before initiation of and during chemotherapy. Treatment decisions must be based on the patient’s clinical picture, but always with the knowledge that any alterations in dose, timing of administration, or substitution of an alternate chemotherapeutic agent may compromise outcomes by lowering the treatment response rate and shortening survival.42
TUBE FEEDING AND TOTAL PARENTERAL NUTRITION
Tube feeding and total parenteral nutrition (TPN) frequently are used in oncology to supplement or replace a regular diet for patients who cannot sustain their usual intake of nutritional requirements. Hyperglycemia is a frequent complication from both of these forms of nutrition. It may be exacerbated by coexisting infection, use of steroids, and physiological responses to the stress of severe illness. Hyperglycemia, if left untreated, can lead to dehydration, diabetic ketoacidosis (DKA), or hyperosmolar hyperglycemic state (HHS). The American Diabetes Association recommendations for insulin dosing for enteral/parental feedings are listed in Table 32.2.43
Table 32.2—Insulin Dosing for Enteral/Parental Feedings
IV, intravenous; SQ, subcutaneous; TDD, total daily dose; TPN, total parenteral nutrition.
Source: American Diabetes Association.43
In individuals with preexisting T2D not previously on insulin, 77% of the patients required insulin to control glycemia during TPN. Doses in this group averaged 100 ±8 units/day.44
On the basis of a randomized controlled study of hospitalized patients with diabetes receiving enteral nutrition (EN), Korystkoski et al.45 found no differences in efficacy or safety using sliding-scale regular insulin alone or with glargine or NPH. For patients receiving continuous EN, administration of a long-acting (glargine) or intermediate-acting NPH insulin twice daily in combination with regular insulin administered every 6 h can be effective at maintaining desired glucose levels. The focus of insulin dosing should be based on the planned administration of nutrition. One suggested approach includes administration of NPH (or glargine or detemir) with subcutaneous regular insulin at initiation of EN followed by regular insulin every 6 h for the duration of the tube feeding. Patients who are eating during the day can receive scheduled or correction doses of rapid-acting insulin according to blood glucose results.46
Patients receiving tube feeding or TPN should have their blood glucose monitored every 4–6 h. Short- or rapid-acting insulin dosed according to an algorithm may be given every 4–6 h to correct for any hyperglycemia.47–49Hypoglycemia is likely to occur if TPN is stopped abruptly. Gradually decreasing the insulin infusion rate at least 1 h before discontinuing TPN reduces the risk of hypoglycemia.49 Extra caution should be used when changing from continuous to bolus feedings in the setting of long-acting basal insulin. Timing the change when the basal insulin action nears its end will help alleviate hypoglycemia. Nurses can be instrumental to helping to develop and implement hypoglycemia protocols for the management of unforeseen interruptions of feeding regimens.
Nursing Implications
Most nurses will encounter patients with both diabetes and cancer, each perhaps compounding management of the other. It may be necessary to improve diabetes control in patients with severe hyperglycemia before the cancer treatment as steroids frequently given in combination with chemotherapy may increase glucose levels further causing electrolyte imbalances, dehydration, and potential ketosis. Chemotherapy may increase glucose as can physical and emotional stress. Hyperglycemia and chemotherapy may cause fatigue, lack of appetite, and little energy, which makes glucose control more challenging.50
Glucocorticoids frequently are used as part of a chemotherapeutic regimen to control nausea and reduce cerebral edema. They also increase insulin resistance, however, and can disrupt the function of β-cells leading to hyperglycemia and overt diabetes. Medications for diabetes may need to be increased or decreased. Often, insulin may need to be initiated as oral agents are no longer adequately controlling the blood glucose.13 In patients with prediabetes, use of glucocorticoids may cause overt diabetes, requiring medication and additional education about coping with another diagnosis. Those at the highest risk for steroid-induced diabetes include those with a family history of diabetes, previous history of gestational diabetes, advanced age, obesity, and high-dose steroid treatment. Patients taking glucocorticoids should be followed closely, particularly if the dosages frequently are adjusted, as this will affect blood glucose levels and can lead to hypoglycemia or more severe hyperglycemia. Nurses can be proactive by educating patients about the importance of reporting glucocorticoid dose changes, increasing blood glucose monitoring during this time, and recognizing the potential need to adjust diabetes medications and insulin.
Nutrition
Patients with diabetes and cancer undergoing chemotherapy face many challenges, including decreased appetite. Nurses can work with patients to increase fluids, and eat foods with higher calories to prevent weight loss.48Chemotherapy may cause nausea, also contributing to decreased intake and dehydration.
Nausea and vomiting are common adverse drug reactions in some chemotherapy regimens. These reactions can occur in anticipation of therapy, acutely during or within 24 h of the therapy, or persistently over an extended period of time after therapy. Breakthrough nausea and vomiting may occur despite prophylactic treatment.
All patients should be screened for a history of nausea and vomiting before initiating any chemotherapy. The history should include nausea and vomiting related to motion sickness, anesthesia, pregnancy, and any previous chemotherapy treatments. It should include the frequency, severity, and duration of episodes, as well as the effect of nausea and vomiting on the patient’s ability to eat and drink. Document all previous treatments for nausea and vomiting, including medications, doses, frequency, and effectiveness of the therapy.
Always consider the differential diagnoses for nausea and vomiting. These diagnoses include but are not limited to metabolic abnormalities (including DKA and HHS), bowel obstruction, infection, hepatic dysfunction, increased intracranial pressure, medication interactions, and radiation therapy.
Before initiating any chemotherapy regimen, consider the emetogenic potential of any agent or combination of agents in conjunction with the patient’s history of nausea and vomiting, and pretreat the patient accordingly. Patients with diabetes should be assessed frequently for nausea and vomiting, hydration status, ability to eat and drink, and glycemic control. Encourage patients to eat small, frequent meals, while avoiding sweet, fatty, salty, or spicy foods that may increase the severity of nausea and vomiting. Treat any breakthrough nausea immediately. Consider increasing the frequency of blood glucose monitoring for any patient with nausea and vomiting or a decreased tolerance to food and drink, especially if a steroid is used to manage emesis.
The risk of hypoglycemia is a major concern in patients who are taking sulfonylureas, other insulin secretagogues, or insulin when food intake is variable, and these medications likely will require adjustment. Eating healthfully is still a goal of treatment for both diseases, as is trying to keep physically active and less sedentary. Focus eating around a healthy diet, such as vegetables, fruits, whole grains, and legumes. Consultation with a registered dietitian knowledgeable about requirements for cancer patients and diabetes is very useful. Patients with cancer often experience physical impairment and fatigue, and one-third to one-half of cancer patients undergoing active treatment for cancer experience pain.51 Help patients plan what type of activity they can tolerate—even walking 10 min several times a day 2–3 times a day is beneficial—or encourage sitting exercises. Whether to continue or stop blood glucose monitoring during treatment is controversial. Blood glucose monitoring becomes more important in these situations to help regulate glucose, preventing hypo- and hyperglycemia. Medications may need to be adjusted as well as the timing and amount of food and liquid intake. Nurses can work with others on the health-care team to advise the timing and scheduling of blood glucose monitoring and to interpret patterns. Some patients and families focus on blood glucose management because it is one way to feel some control over their illnesses. Nurses should determine the patient’s desires and goals in making these decisions. Certainly, in the patient who is terminal, blood glucose monitoring may not be necessary, or the frequency can be curtailed as the goals for blood glucose control become less important. Helping patients to feel better, without the symptoms of hyperglycemia or hypoglycemia is key, so nurses should monitor patients for these symptoms, check glucose periodically, and communicate these concerns to other members of the health-care team.
Psychosocial Impact
Perhaps one of the most difficult issues facing patients with diabetes and cancer is the emotional toll it takes on the individual and the family. Patients may feel anxious, dealing with feelings of guilt, loss of control, anger, fear, and financial stress. Just allowing patients to express their feelings can help alleviate or decrease this stress. In addition, some of the stress may be related to lack of information, knowledge, and skills needed to manage their illnesses.51With a burdened health-care system, patients may feel a lack of support and attention from the health-care system, furthering the emotional impact. Nurses are in the best position to help patients navigate the health-care system, provide emotional support and education, and help patients find community resources that could help them, including social support, pharmacological management, behavioral health resources, education of the family and caregivers, and legal or financial services. Additionally, nurses should recommend peer or counseling support. If symptoms of anxiety, depression, or other psychosocial issues are present, referral to a mental health provider is recommended. If a patient is hospitalized, discharge planning is essential.
Nursing Concerns in the Patient with Diabetes and Cancer
1. Monitor patients on glucocorticoids for symptoms of hyperglycemia; test blood glucose to assess glucose control.
2. Ensure adequate nutritional intake; consider referral to a registered dietitian or certified diabetes educator.
3. Encourage physical activity, as tolerated.
4. Help patient and family to manage medication schedules.
5. Encourage emotional and social support; consider referral to a mental health provider.
6. Promote a healthy lifestyle.
Prevention
Prevention efforts should include diabetes prevention and perhaps cancer prevention as well. As noted, some of the risk factors associated with the development of T2D are also risk factors for the development of certain cancers. The American Cancer Society states that one in three cancer deaths each year are linked to diet and physical activity habits, including being overweight or obese. Another one in three cancer deaths are caused by exposure to tobacco. The Society’s recommendations include keeping a healthy weight throughout life, following a healthy plant-based diet, limiting processed meat, limiting alcohol, controlling weight, completing 150 min of moderate-intensity physical activity or 75 min of intense activity each week, limiting sedentary behaviors, and being aware of risks.52 Other recommendations include following general cancer screening test recommendations, such as yearly mammography for women >40 years old, colonoscopy every 10 years for those >50 years old (or earlier if recommended), yearly guaiac-based fecal occult blood test, cervical cancer testing, and any other cancer screening exams deemed necessary by primary providers.53
In terms of diabetes-linked cancers, nurses should emphasize the modifiable risks of overweight and obesity, sedentary lifestyle, and unhealthy diet specifically for colorectal cancer and breast cancer. It is also important to teach patients to recognize the warning signs of the high-risk cancers and when to report them. Nurses can be alert to these symptoms and changes. Nurses are also the best patient advocates for referral to other members of the health-care team.
SUMMARY
Just having a diagnosis of diabetes requires self-management education, and frequently lifestyle changes that can be challenging. The diagnosis of cancer along with diabetes creates a huge burden on the patient and family and, quite often, increases fear. When patients hear about medications that may be linked to cancer, they are unlikely to want to continue them. Nurses should reassure patients that diabetes medications have not conclusively been linked to cancer. In addition, treatment for cancer can worsen diabetes control. Nurses play many roles in diabetes and cancer treatment, but the most important are to recognize the needs of the individual and family, provide education and support, anticipate potential complications, and work closely with the health-care team to promote the well-being of the patients. Nurses can keep abreast of current research to help patients navigate the various and numerous decisions patients may have to make. Nurses can be advocates for prevention and a healthy lifestyle to decrease cancer risk as well as diabetes and prediabetes and to promote overall health.
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