ABSTRACT

There is increasing evidence of an association between cancer and diabetes mellitus. Patients with type II diabetes are at increased risk of malignancy due to shared risk factors between the two conditions, and people with a diagnosis of cancer may develop new onset diabetes or impaired glycemic control, partly as a result of the systemic anti-cancer treatments (SACT) they receive. Many newer targeted anti-cancer treatments can have off-target metabolic toxicities not seen with conventional chemotherapy agents. Early recognition of diabetes or hyperglycemia in people with cancer can improve outcomes. This chapter aims to summarize these associations, provide an overview of how different SACT modalities can impact on glycemic control, and highlight key recommendations for the management of this complex patient group. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Diabetes mellitus (DM) is a rising global public health emergency, with recent estimates suggesting that over 780 million people globally will be affected by 2045 (1). DM is typically classified into broad categories including type 1 (T1DM), type 2 (T2DM), gestational, monogenic, pharmacologically-induced, endocrinopathy-driven and DM due to pancreatic disease/deficiency (sometimes referred to as type 3c) (2, 3). T2DM is regarded as the most common subtype and is reported to account for over 85% of cases (1). All types of DM can lead to multisystem microvascular (nephropathy, retinopathy, neuropathy) and macrovascular (ischemic heart disease, stroke and peripheral vascular disease) complications, with management of these complications placing a strain upon many health services.

People with a diagnosis of DM are also at higher risk for developing several cancers (4), with reasons for this in part due to shared risk factors between the two, including age, obesity, sedentary lifestyle, and diet (5,6). A recent umbrella review of meta-analyses found that risks of developing most cancers were higher in people with DM compared to those without, with the most convincing evidence seen in breast cancer, intrahepatic cholangiocarcinoma, colorectal cancer, and endometrial cancer. One exception in this study was prostate cancer, where the risk appeared lower in individuals with DM (4). In view of this increased cancer risk in people with DM, some groups even advocate that regular screening for underlying cancer should be part of routine DM assessments (7).

It is estimated that approximately 20% of people with cancer have concurrent diabetes (8). Individuals with cancer are also at an increased risk of developing new onset DM or hyperglycemia, independent of an underlying diagnosis of diabetes, whilst cancer patients with concurrent DM often experience worsening glycemic control (9). Reasons for poor glycemic control in these individuals include complications from systemic anticancer treatments (SACT) along with supportive medications to treat treatment side effects, and symptoms of the underlying malignancy. This chapter aims to summarize the complex relationship between malignancy and DM, particularly the effects of SACT on glycemic control and risk of DM, as well as outlining management guidelines for DM in people with cancer.

DIABETES/HYPERGLYCEMIA AND CANCER OUTCOMES

A number of observational studies have demonstrated that hyperglycemia is associated with poorer overall survival (OS) and increased risk of disease recurrence in a number of malignancies, solid and hematological (10-17), with a number of individual studies, and larger meta-analyses supporting this. One meta-analysis reviewed 12 studies comprising 9,872 people with a diagnosis of cancer without known diabetes. Individuals with hyperglycemia were found to have significantly worse disease-free survival (DFS) (hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.20-3.27) compared to those without, as well as worse OS (HR 2.05, 95% CI 1.67-2.551) (18). A further meta-analysis of 4,241 patients with pancreatic cancer suggested that those individuals with concurrent DM (1,034) have poorer OS (HR 1.16, 95% CI 1.08-1.25) and a higher risk of on-treatment death than those without concurrent DM (19). Furthermore, in a meta-analysis of 8 studies in breast cancer, concurrent DM was found to confer a greater risk of death, and a later stage at presentation, as well as impact on the treatment given (20). People with DM also have a higher prevalence of oral cancers, as well as a higher mortality from these cancers (21).

In addition to this, a number of preclinical studies have suggested that hyperglycemia may specifically attenuate the efficacy of chemotherapy in people with cancer with or without diabetes, which could in part account for these observations (22). For example, hyperglycemia may attenuate chemotherapy-induced reactive oxygen species (ROS) production, which in-turn can diminish the efficacy of treatment (23). In vivo, there are some small series that have demonstrated an association between hyperglycemia and resistance to chemotherapy. A clinical study of 88 people with estrogen-receptor positive breast cancer demonstrated impaired glucose tolerance significantly correlated with disease progression in those patients receiving chemotherapy (24). Furthermore, high blood glucose levels irrespective of an underlying DM diagnosis, were shown to significantly enhance oxaliplatin resistance in individuals with stage III colorectal cancer receiving adjuvant chemotherapy (22). Studies such as these highlight the importance of adequate glycemic control during treatment for cancer to potentially improve outcomes, although these data are mainly from observational studies, with interventional studies lacking.

EFFECT OF DIABETES OR HYPERGLYCEMIA ON QUALITY OF LIFE IN PEOPLE WITH CANCER

Cancer-related symptoms and SACT side effects, such as fatigue, nausea, anorexia and pain can be debilitating to patients. When confounded by symptoms of hyperglycemia, the impact upon an individuals’ quality of life can be significant (25). Furthermore, the impact of a cancer diagnosis, as well as treatment and cancer-related symptoms can have major negative impacts on diabetes self-care (26), with data suggesting that adherence to glucose lowering drugs often decreases in individuals following a cancer diagnosis (27). A cancer diagnosis can also have financial and social impacts upon individuals, affecting access to healthy food and outpatient diabetes services, resulting in lower quality of life and a higher symptom burden (28). A systematic review of 10 studies, demonstrated poorer patient reported outcomes (PROs) in those diagnosed with both cancer and DM compared to having either one of these diseases alone (29).

DIABETES AND RISK OF TREATMENT RELATED TOXICITY

People with DM are known to be at higher risk from infections, and undergoing SACT can exacerbate this, resulting in higher rates of infection and hospitalization observed in those with cancer and DM (30, 31). This in turn leads to higher rates of chemotherapy dose reductions and early treatment cessation (28, 32-34). A meta-analysis of 10 observational studies involving 8,688 cases found that the likelihood of developing chemotherapy-induced neutropenia was higher amongst individuals with DM/hyperglycemia than those without (odds ratio (OR) 1.32, 95% CI 1.06-1.64) (31). Chemotherapy-induced neutropenia poses a significant risk for infection and hospitalization in all people with cancer, with an associated rate of morbidity and mortality which is higher in those with raised blood glucose levels (30). In addition to severe hematological toxicity, more severe rates of non-hematological toxicity have also been associated with hyperglycemia during chemotherapy in people with prostate cancer and lymphoma (35). A single-center retrospective analysis found that individuals with cancer and DM who had good glycemic control had no increased risk of treatment-related complications compared with individuals without DM (36), suggesting that optimal glycemic control during SACT could improve tolerability, thereby reducing rates of admission and dose-limiting toxicity.

Conceivably, people with DM may be more prone to neuro- and nephrotoxic agents due to their underlying predisposition conferred by the DM. Indeed, a previous report suggested that taxane-based chemotherapy regimens resulted in a significantly higher rates of peripheral neuropathy in those with DM compared to those without (74.4% vs. 58.5%) (37). There are no convincing data to suggest that a concurrent cancer diagnosis accelerates the risk of diabetic nephropathy or retinopathy.

EFFECTS OF SYSTEMIC ANTICANCER THERAPIES ON GLYCEMIA

Systemic anti-cancer therapies (SACT) encompass a wide range of treatments including cytotoxic chemotherapy, hormone therapy, targeted therapy, and immunotherapy, many of which can impact upon glycemic control directly or as a result of toxicity management or supportive medications which are given alongside treatment. Several anti-cancer agents have been demonstrated to increase the risk of hyperglycemia as summarized in Table 1, and many can do this even in those without a known diagnosis of DM. People receiving SACT are also at risk of developing a new diagnosis of diabetes. One study demonstrated that 11% of people (15/134) undergoing routine chemotherapy met the criteria for a new diagnosis of diabetes (using the diagnostic criteria as per guidelines from the UK National Institute for Clinical and Healthcare Excellence (NICE) and without a previous known diagnosis) based upon HbA_1c measurements). The majority of these individuals (73%) had been receiving short course steroids with chemotherapy, and 40% were being treated in the curative/adjuvant setting (38). A second prospective cohort study in 90 people taking glucocorticoids as part of therapy protocols for primary brain tumor or metastases, lymphoma, or for bone marrow transplant, found non-DM range hyperglycemia in 58% and DM-range hyperglycemia in 18.9% (39). These individuals with hyperglycemia are also more likely to present with an emergency admission during cancer therapy than those with normoglycemia (40).

HYPOGYCEMIA IN PEOPLE ON SACT

Although anti-cancer therapies and glucocorticoid use lead predominantly to hyperglycemia, there are risks of hypoglycemia that require consideration. People at risk of hypoglycemia should be counselled on the signs and symptoms to be aware of, and of the requirement to inform the driver and vehicle licensing agency should they experience any episodes of hypoglycemia requiring third party assistance.

Poor oral intake and nausea/vomiting from the underlying cancer or treatments put individuals at increased risk of hypoglycemia. Poor glycemic control can cause weight loss and precipitate nutrition impact symptoms (NIS) such as nausea, poor appetite, and altered bowel movements, further increasing the risks of hypoglycemia, particularly when dietary intake has been poor for some time. People with diabetes on an insulin secretagogue (sulfonylureas or meglitinides), or those on insulin, are also at higher risk of hypoglycemia.

In patients with end-stage metastatic disease, and shortened life expectancy, tight glucose control is not indicated, potentially placing individuals at unnecessary risk for hypoglycemia, particularly in those with a poor performance status >2. Individual risk for hypoglycemia and prognosis should be considered and recommended glycemic measurement targets are between 6.0 mmol/L – 15 mmol/L (108 – 225 mg/dl) (117).

People with new onset ICPi-induced insulin deficiency often have labile glucose control (99). More relaxed glucose targets may be required to avoid hypoglycemia wherever possible. Immune checkpoint inhibitors can also induce hypopituitarism leading to secondary adrenal insufficiency. This may lead to hypoglycemia (together with any of the following - hyponatremia, hyperkalemia and hypotension). Adrenalitis leading to primary adrenal insufficiency is very rare. Presentation of adrenal insufficiency ranges from asymptomatic laboratory alterations to the acutely unwell, with management depending on the severity (118). Other causes of adrenal or pituitary deficiency leading to hypoglycemia include metastases at these sites, surgery, irradiation, azole class of anti-fungal medication, and inappropriate abrupt cessation of glucocorticoid medication.

In oncology patients being weaned from long-term steroids, glucose monitoring will need to be continued after glucocorticoid cessation, with doses of anti-diabetic treatments adjusted accordingly, and individuals advised on risks of hypoglycemia. Caution is also required whilst using certain hematological anti-cancer therapies, including lenalidomide (119) and bortezomib (120), which can precipitate hypoglycemia, particularly in people with an underlying diagnosis of diabetes.

All cancer patients at risk from hypoglycemia should receive advice regarding appropriate treatment with 15–20 g of fast-acting carbohydrate, taken immediately (121). Comprehensive guidelines from the Joint British Diabetes Societies for Inpatient Care on the management of hypoglycemia can be found at this reference (122).

MANAGEMENT RECOMMENDATIONS

Despite the effects of hyper- and hypoglycemia in people with diabetes (PWD) and those without known diabetes in cancer, there is a sparsity of guidance on the specific management considerations of these individuals. To address this, collaborative guidelines have recently been produced by the UK Chemotherapy Board (UKCB) and Joint British Diabetes Society for Inpatient Care (JBDS) (123, 124). The scope of these guidelines are to provide advice for the oncology/hemato-oncology and diabetes multidisciplinary teams to manage people with diabetes, commencing anti-cancer/ steroid therapy, as well as identifying individuals without a known diagnosis of diabetes who are at risk of developing hyperglycemia and new onset diabetes. These guidelines are intended for the outpatient management of people with cancer, particularly in the setting of the oncology/hemato-oncology clinic, and provision of advice for individuals at home, but where necessary, may be applied to inpatients as well. Whilst covering these guidelines in detail is beyond the scope of this chapter, key management considerations are summarized in tables 4-9.

Full management guidelines can be found at the UK Chemotherapy Board (UKCB) and Joint British Diabetes Society for Inpatient Care (JBDS) websites.

ADDITIONAL MANAGEMENT CONSIDERATIONS: CHOICE OF DIABETES THERAPEUTIC AGENT

Special consideration should also be given to the non-glycemic effects of hypoglycemic agents, including specific side effects and the impact on weight. Although weight reduction is associated with improvement in glycemic and metabolic profile in people with type 2 diabetes and is a key consideration in the choice of therapy, significant weight loss would usually be an unwanted effect in the oncology population. Indeed, weight gain is often used as a metric of improving nutritional state, especially in cancer related cachexia. This also has implications when counselling people with cancer about dietary choices when there is an additional cancer diagnosis. It is imperative that personalized advice is offered by healthcare professionals considering the global impact on the individual of any dietary or even lifestyle advice. SGLT2 inhibitors and GLP-1 agonists, for their potential weight reduction effects, are therefore less attractive options in the oncology setting. Insulin and sulfonylureas, on the other hand, offer an anabolic effect and therefore may be more desirable. Gastrointestinal side effects are common among hypoglycemic agents including metformin, DPP4 inhibitors, and GLP-1 agonists, and have the potential to complicate issues with nausea, vomiting, and oral intake from the underlying cancer and its treatment. Similarly, poor oral intake and nephrotoxic effects of certain SACT, added to a potential osmotic diuretic effect of SGLT2 inhibitors, could also increase the risk of acute kidney injury. The associated risk of genital tract infections with SGLT2 inhibitors would also be an additional consideration especially within an immunocompromised population (125). The impact and significance of these non-glycemic effects in the oncology population clearly differ to that of the general population, therefore highlighting the importance of a personalized approach with regular review of patients’ diabetes treatment through their oncology journey.

CONCLUSIONS

It is common practice in oncology to initiate systemic anti-cancer therapy (including chemotherapy, targeted treatment, immunotherapy and steroids) in people with pre-existing diabetes. Diabetes, or risk of developing diabetes are by no means a contraindication to treatment but treating clinicians should be aware of the risks to patients, and counsel them appropriately. As more sophisticated anti-cancer treatments become licensed for use, the metabolic effects of these treatments will become better understood, and oncology teams should utilize and collaborate with endocrinology and primary care services to minimize the risks to individuals from poor glycemic control and diabetes. The recent publication of specific guidelines should act as a reference aid for clinicians and wider healthcare professionals to aid in risk recognition, diagnostic and screening for treatment induced diabetes, and provide the tools to appropriately manage these individuals and reduce the risks of complications.

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