In Brief Diseases Diabetes and Coexisting / From Research to Practice

Diabetes and cancer are two diagnoses that individually overwhelm both patients and clinicians. Approximately 8–18% of people with cancer have diabetes. Together, these two diseases can pose formidable challenges to clini- cians caring for this difficult patient population. Unfortunately, our knowl- edge of this topic is limited by insufficient evidence to determine how best to manage diabetes while simultaneously treating cancer. This article seeks to review some of the most common problems encountered by clinicians caring for these patients.

Clinical Challenges in Caring for Patients With Diabetes and Cancer

Diabetes and cancer are two diagnoses not be explained by differences in that individually overwhelm both comorbidity, income, age, access to patients and clinicians. Approximately care, or use of estrogen therapy. Helen M. Psarakis, RN, APRN 8–18% of people with cancer have Instead, it was attributed to time con- diabetes.1 Together, these two diseases straints during office visits for com- can pose formidable challenges to clin- plex chronic disease care, perceptions icians caring for this difficult patient of decreased life expectancy by both population. Unfortunately, our knowl- patients and health care providers, edge of this topic is limited by insuffi- and sociocultural barriers to health cient evidence to determine how best education. This should serve as a to manage diabetes while simultane- reminder for clinicians to question ously treating cancer. This article seeks patients about their primary health to review some of the most common care as routinely as they are screened problems encountered by clinicians for diabetes complications. caring for these patients. This trend of decreased prevention services is disturbing given the evi- Cancer Screening and Prevention dence to suggest that insulin resistance Several studies published within the and diabetes are linked to higher inci- past decade demonstrate that patients dences of some cancers. Researchers with a chronic disease are less likely hypothesize that exposure to hyper- to receive preventive services, such as glycemia, elevated insulin concentra- cancer screenings, than their counter- tions, and the growth-promoting parts without diabetes.2–5 A recent effects of IFG-I may stimulate the retrospective study addressed cancer development or progression of cancer. screening in patients with diabetes.6 People with type 2 diabetes are at After examining the mammography higher risk for developing breast, pan- rates of 69,168 Canadian women creatic, liver, kidney, endometrial, and with diabetes and 663,519 Canadian colon cancers. Patients with type 1 women without diabetes, the authors diabetes are more likely to develop concluded that patients with complex cervical and stomach cancers. chronic diseases are 32% less likely to Several studies have also demon- receive this routine cancer screening, strated that patients with diabetes and even though they see primary care cancer have a poorer prognosis com- and specialty physicians more fre- pared with those without diabetes. quently than their counterparts with- Diabetes and hyperglycemia are asso- out diabetes. The discrepancy could ciated with higher infection rates, 157 Diabetes Spectrum Volume 19, Number 3, 2006 shorter remission periods, and shorter the strongest predictors for glucocorti- or hyperosmolar hyperglycemic state median survival times, as well as high- coid-induced diabetes.12 (HHS) if left untreated. er mortality rates.7–10 Treatment of hyperglycemia result- Adding regular insulin to the TPN ing from glucocorticoids depends on solution can help control blood glu- Cancer Treatment the type of diabetes, severity of the cose levels. Initial doses are usually 1 Chemotherapeutic Agents elevated blood glucose levels, and unit per 10 g of carbohydrate. The Patients with diabetes may present dose and duration of the therapy. dose should be titrated daily until unique challenges to clinicians making Giving steroids in multiple doses glycemic control is attained. Using a cancer treatment decisions. Patients throughout the day instead of a single lower carbohydrate formula will help with long-standing diabetes or a histo- bolus dose or administering the total with glycemic control in enterally fed ry of poorly controlled diabetes may daily steroid dose intravenously over patients. present for cancer treatment with pre- 24 hours can assist in controlling These patients may also benefit existing renal, cardiac, or neuropathic hyperglycemia. Patients with pre- from the use of basal insulin. The type complications. Several chemotherapeu- existing diabetes may be kept on their of basal insulin used depends on the tic agents are known to cause or exac- oral hypoglycemic agents and moni- duration of the tube feeding. Some erbate these conditions. For example, tored carefully. However, these clinicians prefer glargine for continu- cisplatin is known to cause renal insuf- agents are usually inadequate for ous tube feeding. However, NPH or ficiency, and the anthracyclines may managing hyperglycemia in this set- detemir given 2–3 times per day may cause cardiotoxicity. Cisplatin, pacli- ting. Patients using insulin before glu- work as well and allow for a quicker taxel, and vincristine may be neuro- cocorticoid therapy will typically titration of the insulin dose. The toxic. Unfortunately, many of these require both basal and preprandial University of Vermont is successfully side effects from chemotherapeutic insulins. These patients may require using a protocol of 70/30 (NPH/regu- agents are permanent. two to three times their usual dose(s) lar) given every 8 hours. The starting Successful cancer treatment usual- of insulin. Insulin is the preferred dose calculation varies based on ly requires at least 85% of the drug for managing steroid-induced or renal/hepatic/cardiac dysfunction, chemo-therapeutic dose be given. exacerbated hyperglycemia in patients obesity, open wounds/infection, or Patients with diabetes must be care- with known diabetes. Many patients steroid therapy. NPH and the fully monitored before initiation of will require basal and prandial bolus NPH/regular 70/30 mix also offer an and during chemotherapy. Treatment insulins to attain adequate glycemic easier transition from continuous to decisions must be based on the control.12–14 timed or bolus tube feeding because a patient’s clinical picture, but always Insulin doses may be estimated dose can be eliminated when the feed- with the knowledge that any alter- based on the patient’s weight and ings are discontinued. Patients receiv- ations in dose, timing of administra- administered subcutaneously. Use of ing tube feeding or TPN should have tion, or substitution of an alternate an intravenous insulin infusion is their blood glucose monitored every chemotherapeutic agent may com- another quick way to lower blood 4–6 hours. Short- or rapid-acting promise outcomes by lowering the glucose as well as estimate the total insulin dosed according to an algo- treatment response rate and shorten- daily insulin requirement in insulin rithm may be given every 6 hours to ing survival.10 naive patients. However, many hospi- correct for any hyperglycemia.18–20 tals are resistant to using intravenous Hypoglycemia is likely to occur if Glucocorticoids insulin drips outside of the intensive TPN is stopped abruptly. Gradually The use of glucocorticoids in patients care setting because of fear of hypo- decreasing the infusion rate at least 1 with pre-existing diabetes typically glycemia. Hourly glucose monitoring hour before discontinuing TPN wreaks havoc on postprandial and insulin drip rate titrations place reduces the risk of hypoglycemia.20 glycemic control. Unfortunately, glu- an added burden on the nursing staff. cocorticoids are routinely used in Regardless of the route or setting, Nausea and Vomiting many cancer treatment protocols. insulin doses should be titrated daily Nausea and vomiting are common Glucocorticoid treatment for cancer as needed and should be tapered as adverse drug reactions in some patients usually consists of short-term glucocorticoid therapy is tapered to chemotherapy regimens. These reac- therapy at a high dose. Lower-dose avoid hypoglycemia.11–17 tions can occur in anticipation of ther- steroids are also used to prevent apy, acutely during or within 24 chemotherapy-induced nausea and Tube Feeding and Total Parenteral hours of the therapy, or may persist vomiting. All patients should be Nutrition over an extended period of time after screened for diabetes before initiating Tube feeding and total parenteral therapy. Breakthrough nausea and glucocorticoid therapy and routinely nutrition (TPN) are frequently used in vomiting may occur, despite prophy- monitored thereafter. These medica- oncology to supplement or replace a lactic treatment. tions raise blood glucose through regular diet for patients who cannot All patients should be screened for increased insulin resistance, gluconeo- sustain their usual intake of nutrition- a history of nausea and vomiting genesis, glycogenolysis, and decreased al requirements. Hyperglycemia is a before initiation of any chemotherapy. insulin production and secretion.11 frequent complication from both of The history should include nausea and It is also common for patients to be these forms of nutrition. It may be vomiting related to motion sickness, diagnosed with diabetes while receiv- exacerbated by coexisting infection, anesthesia, pregnancy, and any previ- ing glucocorticoid therapy. Family the use of steroids, and the physiologi- ous chemotherapy treatments. It history of diabetes, a personal history cal response to the stress of severe ill- should also include the frequency, of gestational diabetes, increased age, ness. Hyperglycemia can lead to dehy- severity, and duration of episodes, as obesity, and high doses of steroids are dration, diabetic ketoacidosis (DKA), well as the effect of nausea and vomit- 158 Diabetes Spectrum Volume 19, Number 3, 2006 ing on the patient’s ability to eat and Before initiating any chemotherapy Patients with diabetes should be Diabetes and Coexisting Diseases / From Research to Practice drink. Document all previous treat- regimen, consider the emetogenic assessed frequently for nausea and ments for nausea and vomiting, potential of any agent or combination vomiting, hydration status, ability to including medications, doses, frequen- of agents in conjunction with eat and drink, and level of glycemic cy, and effectiveness of the therapy. the patient’s history of nausea and control. Encourage patients to eat Always consider the differential vomiting and pretreat the patient small, frequent meals, avoiding diagnoses for nausea and vomiting. accordingly. Tables 1 and 2, created sweet, fatty, salty, or spicy foods These diagnoses include but are not by Yale New Haven Hospital’s that may increase the severity of limited to metabolic abnormalities Oncology Nursing and Pharmocology nausea and vomiting. Treat any (including DKA and HHS), bowel Services, rank chemotherapy agents in breakthrough nausea. Consider obstruction, infection, hepatic dys- order of those most likely to induce increasing the frequency of blood function, increased intracranial pres- emesis in adult and pediatric patients glucose monitoring for any patient sure, medication interactions, and along with the appropriate antiemetic with nausea and vomiting or a radiation therapy. treatment. decreased tolerance to food and Table 1. Yale New Haven Hospital Guidelines for the Control of Chemotherapy-Induced Emesis in Adult Patients

Emetogenic Level Frequency of Emesis Chemotherapy Agent Antiemetic Dose and Schedule

5 > 90% Carmustine > 250 mg/m2 Ondansetron, 8 mg i.v. Cisplatin ≥ 50 mg/m2 Cyclophosphamide > 1,500 mg/m2 Dexamethasone 20 mg i.v., pretreatment Dacarbazine Dactinomcin At 8–12 hours after treatment or Mechlorethamine at bedtime, give: Streptozocin Any agent used at myeloablative doses Prochlorperaxine, 10 mg i.v./orally or Metoclopramide, 20–40 mg i.v./orally

Lorazepam 0.5–1 mg i.v./orally may be given pre- or posttreatment if needed

4 60–90% Carboplatin Ondansetron 8 mg i.v. Carmustine ≤ 250 mg/m2 Cisplatin < 50 mg/m2 Dexamethasone 20 mg i.v., pretreatment Cychlophosphamide > 750–1,500 mg/m2 Cytarabine > 1 g/m2 At 8–12 hours after treatment or at bedtime, give: Doxorubicin > 60 mg/m2 Ifosfamide > 1,000 mg/m2 Prochlorperaxine 10 mg i.v./orally Irinotecan or Melphalan i.v. Metoclopramide 20-40 mg i.v./orally Methotrexate > 1,000 mg/m2 Oxaliplatin Lorazepam 0.5–1 mg i.v./orally may be given pre- or a Procarbazine (orally) posttreatment if needed

3 30–60% Cyclophosphamide ≤ 750 mg/m2 Ondansetron 8 mg i.v., pretreatment Cyclophosphamide orallya Doxorubicin 20–60 mg/m2 Dexamethasone 10–20 mg i.v., pretreatment Epirubicin ≤ 90 mg/m2 Gemcitabine Hexamethylmelamine orallya Idarubicin Ifosfamide ≤ 1000 mg/m2 Lomustine orallyb Methotrexate 250–1,000 mg/m2 Mitoxantrone

2 10–30% Docetaxel Dexamethasone 4–8 mg i.v./orally, pretreatment Etoposide 5-Fluorouracil < 1,000 mg/m2 Liposomal doxorubicin Methotrexate > 50–249 mg/m2 Mitomycin Paclitaxel Teniposide Thiotepa Topotecan Continued on page 160 159 Diabetes Spectrum Volume 19, Number 3, 2006 Table 1. Yale New Haven Hospital Guidelines for the Control of Chemotherapy-Induced Emesis in Adult Patients, cont’d

Emetogenic Level Frequency of Emesis Chemotherapy Agent Antiemetic Dose and Schedule

1 < 10% Asparaginase No routine pretreatment recommended Bleomycin Busulfan orally Chlorambucil orally 2-Chlorodeoxyadenosine Fludarabine Hydroxyurea Methotrexate ≤ 50 mg/m2 Melphalan orally 6-Mercaptopurine Tamoxifen 6-Thioguanine Vinblastine Vincristine Vinorelbine

aThe most highly emetogenic agent in the combination should be identified, and the contribution of other agents should be considered by using the following rules: 1) level 1 agents do not contribute to the emetogenicity of a given regimen; 2) adding one or more level 2 agents increases the eme- togenicity of the combination by one level greater than the most emetogenic agent in the combination; 3) adding level 3 and level 4 agents increases the emetogenicity of the combination by one level per agent. bOral chemotherapeutic agents that are highly emetogenic at high doses and may be less emetogenic in lower doses given over a longer period (i.e., 2 weeks). Oral procarbazine and cyclophosphamide are usually given in combination chemotherapy regimens that include a moderate dose of corti- costeroid (prednisone), which can serve as a sufficient antiemetic. On the other hand, the combination of moderate-risk emetogenic drugs can result in high emetogenic potential and should be treated accordingly. Although given orally, lomustine is highly emetogenic and should be treated with the listed premedication. Reprinted from Yale New Haven Hospital: Nausea and vomiting related to cancer chemotherapy. In Clinical Practice Manual. New Haven, Conn., Yale New Haven Hospital, 2005

drink, especially if a steroid is used untenable situation. Insulin and oral to manage emesis. hypoglycemic agents should still be References Adjust antihyperglycemic medica- used in “comfort care” or “palliative 1Ko C, Chaudhry S: The need for a multidiscipli- tion doses accordingly. Consider using care” patients because the signs and nary approach to cancer care. J Surg Res a short-acting secretagogue (nateglin- symptoms of uncontrolled hyper- 105:53–57, 2002 ide or repaglinide) instead of a sul- glycemia decrease quality of life. A 2Beckman T, Cuddihy R, Scheitel S, Naessens J, fonylurea (glimepiride, glipizide, gly- blood glucose goal of < 200 mg/dl Killian J, Pankratz V: Screening mammogram utilization in women with diabetes. Diabetes buride) for postprandial glycemic con- minimizes the risk of polyuria, poly- Care 24:2049–2053, 2001 trol. Advantages include dosing inter- dipsia, electrolyte imbalance, and vals that can be timed with meals or dehydration and may be a realistic 3Kief C, Funkhouser E, Fouad M, May D: Chronic disease as a barrier to breast and cervi- held when patients are unable or goal for some patients. Clinicians cal cancer screening. J Gen Intern Med unwilling to eat. Nateglinide and should elicit patients’ opinions and 13:357–365, 1998 repaglinide are also much quicker to adhere to their wishes when making 4Fontana S, Baumann L, Helberg C, Love R: The peak and have a shorter half-life than treatment decisions. These decisions delivery of preventive services in primary care the sulfonylureas (Table 3). Rapid- should be reevaluated and revised with practices according to chronic disease status. Am acting insulins, such as aspart, gluli- each significant change in patients’ J Public Health 87:1190–1196, 1997 sine, and lispro, have similar advan- clinical picture and always within the 5Redelmeier D, Tan S, Booth G: The treatment tages as the nonsulfonylurea secreta- context of the patients’ overall goals. of unrelated disorders in patients with chronic gogues but can also be dosed immedi- medical diseases. N Eng J Med 338:1516–1520, ately after a meal. Rapid-acting Conclusion 1998 insulin is also easier to titrate to pre- Overall, the treatment of and therapies 6Lipscombe L, Hux J, Booth G: Reduced screen- cisely cover the amount of carbohy- for diabetes in the setting of cancer ing mammography among women with diabetes. drate consumed during meals, thus present a major challenge for clini- Arch Intern Med 165:2090–2095, 2005 affording patients more flexibility in cians. Maintaining adequate glucose 7Bloomgarden Z: Diabetes and cancer. Diabetes food selections and quantity. control reduces the incidence of infec- Care 24:780–781, 2001 tion in at-risk patients with cancer. 8Bloomgarden Z: Second World Congress on the Blood Glucose Management During Sustaining adequate nutrition and pro- Insulin Resistance Syndrome: mediators, pedi- End-of-Life Care viding appropriate calories for patients atric insulin resistance, the polycystic ovary syn- Glycemic control goals may become receiving chemotherapy demands care- drome, and malignancy. Diabetes Care less stringent but should not be ful glucose control with whatever ther- 28:1821–1830, 2005 ignored during end-of-life care. Some apy improves the clinical situation. 9Balkau B, Kahn H, Courbon D, Eschwege E, patients may desire tight glycemic con- Having an understanding of the com- Ducimetiere P: Hyperinsulinemia predicts fatal trol as a means of exerting some plexities of both diseases is necessary liver cancer but is inversely associated with fatal cancer at some other sites. Diabetes Care degree of control over an otherwise to achieve the best outcome. 24:843–849, 2001 160 Diabetes Spectrum Volume 19, Number 3, 2006 Table 2. Yale New Haven Hospital Guidelines for the Control of Chemotherapy-Induced

Emesis in Pediatric Patients Diabetes and Coexisting Diseases / From Research to Practice

Emetogenic Level Frequency of Emesis Chemotherapy Agent Antiemetic Dose and Schedule

High > 90% Busulfan intravenously Ondansetron, 0.15 mg/kg i.v./orally 30 minutes pre- Carmustine chemotherapy, then every 4 hours for 2 additional doses. Cisplatin > 75 mg/m2 (alternatively, ondansetron, 0.45 mg/kg 30 minutes pre- Cisplatin < 75 mg/m2* chemotherapy for one dose daily) Cyclophosphamide ≥ 1,250 mg/m2 + Dacarbazine ≥ 500 mg/m2 Dexamethasone, 8 mg/m2 i.v./orally pre-chemotherapy, Ifosfamide/Carboplatin or then 4 mg/m2 i.v./orally every 6 hours Cisplatin/Etoposide (ICE) Repeat on each day of chemotherapy Lomustine > 60 mg/m2 *Consider ondansetron as above plus dexamethasone pre- Melphalan intravenously chemotherapy only Methotrexate ≥ 10,000 mg/m2 Mitoxantrone > 15 mg/m2 For breakthrough nausea and vomiting, consider the fol- Any agent used at myeloablative doses lowing agents: Diphenhydramine 0.5 mg/kg i.v. (may increase to 1 mg/kg, to a maximum 50 mg/dose) + Promethazine, 0.5 mg/kg i.v. (maximum 25 mg/dose) every 6 hours as needed or Chlorpromazine, 0.55 mg/kg i.v./orally (maximum 40 mg/dose), may repeat every 4–6 hours or Lorazepam, 0.05 mg/kg i.v. (maximum 3 mg/dose), may repeat every 8–12 hours or Dexamethasone, 5–10 mg/m2 i.v./orally, may repeat every 12 hours as needed

If one or more of these agents fails, consider a single dose of ondansetron, 0.15 mg/kg i.v.

For delayed nausea and vomiting associated with cisplatin or cyclophosphamide, consider treatment with one of the following 12–24 hours postchemotherapy: chlorpro- mazine, lorazepam, or ondansetron

Moderate 30–60% Carboplatin Ondansetron, 0.15 mg/kg i.v./orally 30 minutes pre- Cyclophosphamide i.v. < 1,250 mg/m2 chemotherapy, then every 4 hours for 2 additional doses Cytarabine ≥ 1 g/m2 (alternatively, ondansetron, 0.45 mg/kg 30 minutes pre- Dactinomycin chemotherapy for one dose daily) Daunorubicin Doxorubicin Add as needed dexamethasone (8 mg/m2) prechemothera- Idarubicin py, then 4 mg/m2 every 6 hours if ondansetron alone fails Ifosfamide Methotrexate 250–10,000 mg/m2 Mitoxantrone ≤ 15 mg/m2

Low 10–30% Cytarabine < 1 g/m2 Dexamethasone, 5–10 mg/m2 i.v./orally prechemotherapy Etoposide or Fluorouacil < 1,000 mg/m2 Ondansetron, 0.15 mg/kg i.v./orally prechemotherapy Paclitaxel Teniposide Topotecan

Very Low < 10% Asparaginase No antiemetic prophylaxis necessary Bleomycin Cladribine Corticosteroids Cyclophosphamide orally Hydroxyurea Mercaptopurine Methotrexate ≤ 250 mg/m2 Thioguanine orally Vinblastine Vincristine *In multiple agent regimens, the most highly emetogenic agent should be identified. Very low level (< 10%) agents do not contribute to emetogenicity of combination regimens. Adding one or more low-level (10–30%) agent(s) increases emetoginicity of the combination by one level more than the most emetogenic agent. Reprinted from Yale New Haven Hospital: Nausea and vomiting related to cancer chemotherapy. In Clinical Practice Manual. New Haven, Conn., Yale New Haven Hospital, 2005 161 Diabetes Spectrum Volume 19, Number 3, 2006 Table 3. Comparison of Sulfonylureas and Nonsulfonylurea Secretagogues*

Agent Dose (mg) Dose Interval Peak (hours) Half-life (hours) Duration (hours) Glyburide 2.5, 5 Daily, twice daily 4 10 12–24 Micronized 1.5, 3, 6 Daily, twice daily 2 4 12–24 gyburide Glipizide 5, 10 Daily, twice daily 1–3 2–4 12–24 Glipizide-GITS 2.5, 5, 10 Daily 6–12 N/A 24 Glimepiride 1, 2, 4 Daily 2–3 9 24 Nateglinide 60, 120 Three times daily 0.3 1 4 with meals Repaglinide 0.5, 1, 2 Three or four times 1 1 4–6 daily with meals

*Adapted from Inzucchi SE: Diabetes Facts and Guidelines 2006. New Haven, CT: Yale University School of Medicine, 2006

10Richardson L, Pollack L: Influence of type 2 14Childs B, Cypress M, Spollett G (Eds.) In Improving Inpatient Diabetes Care: A Call to diabetes on the development, treatment and out- Complete Nurse’s Guide to Diabetes Care. Action Conference. Washington, D.C., 2006. p. comes of cancer. Nat Clin Pract Oncol 2:48–53, Alexandria, Va., American Diabetes Association, 145–149 2005 2005, p. 320–322 19Lyman B: Metabolic complications associated 15 11Childs B, Cypress M, Spollett G (Eds.): Hirsch I, Braithwaite S, Verderese C: Practical with parenteral nutrition. J Infusion Nurs Complete Nurse’s Guide to Diabetes Care. Management of Inpatient Hyperglycemia. 25:36–44, 2002 Lakeville, CT, Hilliard Publishing, 2005, p. 30 Alexandria, Va., American Diabetes Association, 20McMahon M, Rizza R: Concise review for pri- 2005, p. 320 16Trence D: Management of patients on chronic mary-care physicians: nutrition support in hospi- 12Clement S, Braithwaite SS, Magee M, Ahmann glucocorticoid therapy: an endocrine perspective. talized patients with diabetes mellitus. Mayo Clin Prim Care Clin Office Pract 30:593–605, 2003 Proc 71:587–594, 1996 A, Smith EP, Schafer RG, Hirsch IB: Management of diabetes and hyperglycemia in 17Braithwaite S, Barr W, Rahman A, Quddusi S: hospitals. Diabetes Care 27:553–591, 2004 Managing diabetes during glucocorticoid thera- Helen M. Psarakis, RN, APRN, is a py. Post Grad Med 104:163–166, 1998 13Volgi J, Baldwin D: Glucocorticoid therapy and diabetes clinical nurse specialist at diabetes management. Nurs Clin North Am 18Leahy J: Insulin management of diabetic Yale New Haven Hospital in New 36:333–339, 2001 patients on general medical and surgical floors. Haven, Conn.

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