Everolimus Causing Severe Hypertriglyceridemia and Acute Pancreatitis

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  • a From Stanford Cancer Institute, Stanford, California, and Chao Family Comprehensive Cancer Center, University of California, Irvine, California.

Everolimus is an mTOR inhibitor commonly used to treat metastatic pancreatic neuroendocrine tumors (pNETs) and renal cell carcinoma, and for posttransplant immunosuppression. This report presents a case of a 36-year-old man being treated with everolimus for a metastatic pNET who developed severe hypertriglyceridemia and acute pancreatitis. The incidence of hypertriglyceridemia reported in large prospective randomized trials is reviewed and the management of hypertriglyceridemic pancreatitis is discussed. Careful monitoring of triglyceride levels and dose adjustments of everolimus together with lipid-lowering therapy can allow patients to continue this medication. Because there are increasing indications for the use of everolimus, prescribing oncologists must be cognizant of the common and serious side effects.

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Release date: January 11, 2013; Expiration date: January 11, 2014.

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Describe the rationale for the management methods used in this case presentation
  • Describe the ideal management of a patient taking everolimus, causing severe hypertriglyceridemia and acute pancreatitis

Case Report

A 36-year-old man with a metastatic pancreatic neuroendocrine tumor (pNET) being treated with everolimus at 10 mg daily for the past 2 months presented to the emergency department with severe midepigastric pain of 12 hours duration. The pain was nagging in nature and radiated to the left flank but not the back. He had 6 episodes of nonbilious, nonbloody emesis. He had one prior episode of similar pain approximately 2 weeks ago, which resolved with oxycodone. Initial evaluation was notable for a tender right upper quadrant and epigastrium but no rebound or guarding.

He was initially diagnosed with pNET 2 years prior, when he presented with unintentional weight loss of 25 pounds and a left neck mass. Workup found a pancreatic mass with bulky metastases to the liver and lymph nodes. Biopsies of the pancreatic mass, liver lesion, and a supraclavicular lymph node all found a well-differentiated pNET with a Ki-67 of 10% to 15%. Bone scan showed metastases to 2 vertebral bodies. He had markedly elevated serum levels of chromogranin A (3250 ng/mL; normal <225), glucagon (650 pg/mL; normal <80), serotonin (895 ng/mL; normal <230), gastrin (936 pg/mL; normal <100), and pancreatic polypeptide (5300 pg/mL; normal <249).

Because of his rapid onset of symptoms, he was started on chemotherapy with monthly capecitabine and temozolomide in hopes of achieving tumor regression. He also received zoledronic acid for prophylaxis of skeletal events. He developed back pain, for which he had radiation therapy and vertebroplasty to the T12 vertebral body. He had stable disease through 7 cycles but then presented with acute abdominal pain attributed to enlarging liver metastases with presumed intratumoral bleed.

He was switched to a regimen of capecitabine, oxaliplatin, and bevacizumab every 21 days. Bevacizumab was omitted for the first 2 cycles because of recent intratumoral bleeding, and oxaliplatin was held after 4 cycles because of neuropathy. He completed 6 cycles, and repeat imaging showed stable disease. The patient wished to stop therapy because of travel plans and because he was developing worsening hand-foot syndrome. After a 4-month chemotherapy break, scans showed stable disease but he became increasingly symptomatic with abdominal discomfort, nausea, altered bowel habits, and chest and back pain. The authors therefore initiated therapy with everolimus. After starting everolimus he noted improvement in pain and diarrhea. He had side effects of fatigue, stomatitis, a pustular rash on his fingers and scalp, and mild thrombocytopenia. He had been on everolimus for approximately 2 months at the time of hospitalization.

The patient was otherwise healthy with no medical problems, including no personal or family history of hypertriglyceridemia. He did not consume alcohol or smoke tobacco. His triglyceride level 1 month before hospitalization was 251 mg/dL (normal <150). His medications on hospitalization were everolimus at 10 mg daily and omeprazole at 40 mg daily.

Laboratory results showed normal liver enzymes and a lipase of greater than 400 U/L (normal, 22-51 U/L) and amylase greater than 800 U/L (normal, 31-99 U/L). Nonfasting laboratory results showed a cholesterol level of 325 mg/dL (normal, <200 mg/dL) with triglycerides of greater than 1000 mg/dL (grade 4 hypertriglyceridemia per NCI Common Terminology Criteria for Adverse Events, version 4.0).1 A CT scan of the abdomen showed peripancreatic fat stranding. A mass was found in the head of the pancreas, and the liver metastases were slightly smaller compared with prior imaging. He was therefore diagnosed with acute pancreatitis secondary to hypertriglyceridemia.

The patient was managed supportively with bowel rest, intravenous fluids, and pain management. Everolimus was held. Prophylactic antibiotics were not indicated. The pain resolved after 24 hours and he was started on a clear liquid diet, which was advanced as tolerated. Lipase decreased to 172 U/L and triglycerides to 607 g/dL. He was not started on antihyperlipidemics and did not require apheresis. He was hospitalized for a total of 3 days. He was eating a regular diet at the time of discharge.

His triglycerides were monitored closely and they returned to normal levels (Figure 1). One month after hospitalization, everolimus was reintroduced at a lower dose of 5 mg daily. He was concurrently started on fenofibrate at 145 mg daily. His triglyceride level began to rise slowly and he was advised to stop everolimus after approximately 2 months. A follow-up CT at that time showed stable disease.

His triglyceride level continued to rise even after discontinuation of everolimus. The patient also inadvertently discontinued fenofibrate. Fenofibrate was restarted and his triglyceride level gradually returned to normal. He was then restarted on everolimus at the 5-mg dose.

Discussion

Everolimus is an inhibitor of mTOR, a serinethreonine kinase downstream of the PI3K/AKT pathway that is critical for cell growth and angiogenesis. Everolimus binds to an intracellular protein, leading to inhibition of mTOR kinase activity. Additionally, everolimus inhibits expression of hypoxia-inducible factor and reduces vascular endothelial growth factor (VEGF) expression.

Everolimus was initially approved by the FDA in 2009 for the second-line treatment of advanced renal cell carcinoma. Subsequently, it has received approval for use in subependymal giant-cell astrocytomas associated with tuberous sclerosis (2010), progressive pNETs (2011), and renal angiomyolipoma with tuberous sclerosis complex (2012). It has been shown to also be effective in improving progression-free survival in patients with hormone receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. Common side effects of everolimus include stomatitis, rash, diarrhea, fatigue, and upper respiratory tract infections.2 The common grade 3 or 4 adverse events are stomatitis, anemia, and hyperglycemia.

Recent phase III studies across several tumor types have shown that hypertriglyceridemia is a common side effect of everolimus therapy (Table 1). In the landmark trial for renal cell cancer (RECORD-1), 71% patients taking everolimus at 10 mg daily had hypertriglyceridemia, including 2% with grade 3 elevation in triglycerides.3,4 Notably, 30% of patients on placebo also had hypertriglyceridemia but all were grade 1 or 2. In the RADIANT-3 trial for pNETs, 39% of patients on everolimus had elevated triglyceride levels but none of grade 3 or 4 severity.5 In the recent BOLERO-2 trial in patients with advanced breast cancer, 50% of patients receiving everolimus and exemestane were reported to have increased triglycerides, with 0.8% developing grade 3 hypertriglyceridemia.6 Similarly, in a phase III trial using everolimus to treat renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis, 79 patients received everolimus, of which 52% developed significant hypertriglyceridemia.7

Figure 1
Figure 1

Triglyceride and lipase levels over time.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0003

Few studies have reported an association between everolimus and pancreatitis. In a phase I study in patients with metastatic clear cell renal cell carcinoma, 1 patient (5%) on combination treatment with everolimus at 5 mg daily and sorafenib at 400 mg twice daily developed grade 2 pancreatitis.8 Pancreatitis is not otherwise reported in the studies listed in Table 1.

A meta-analysis of mTOR inhibitors used in immunosuppression after kidney transplant shows that patients taking mTOR inhibitors had higher triglycerides and cholesterol, and were more likely to be taking lipid-lowering medications.9 This was also observed in patients on everolimus after other organ transplants, such as liver and lung.10,11 Everolimus dosage in the solid organ transplant setting is typically less than 4 mg daily.

The pathogenesis of hypertriglyceridemia associated with mTOR use is poorly understood but may be related to reduced degradation of apolipoprotein B100. Apolipoprotein B100 is formed in the liver and is essential to the assembly of very low-density lipoproteins.9 Additionally, everolimus may lower levels of lipoprotein lipase activity and increase free fatty acid levels, which can contribute to dyslipidemia. Hypertriglyceridemia may be primary, which includes familial hyperlipoproteinemias from Fredrickson class I, III, and V, or secondary, caused by uncontrolled diabetes, alcoholism, medications, hypothyroidism, pregnancy, and exogenous estrogen use.

Hypertriglyceridemia is the third most common cause of acute pancreatitis, after alcohol and gallstones, and has been reported to be associated with 1% to 38% of acute pancreatitis cases.12 Typically, a serum triglyceride level of more than 1000 mg/dL increases the likelihood of pancreatitis. The clinical presentation of acute pancreatitis precipitated by hypertriglyceridemia is similar to that from other causes, with patients presenting with abdominal pain, nausea, and vomiting. The mechanism by which hypertriglyceridemia leads to acute pancreatitis is unclear, but is believed to be related to the impaired clearance of chylomicrons, leading to pancreatic capillary hyperviscosity, which may lead to ischemia. Alternative hypotheses suggest that pancreatic lipase hydrolyzes excess triglycerides, causing damaging free fatty acids to accumulate in the pancreas, or that triglycerides themselves contribute to inflammation within the pancreas.

Table 1

Incidence of Hypertriglyceridemia in Phase III Studies of Everolimus

Table 1

No formal guidelines are available on the management of hypertriglyceridemic pancreatitis. As with other causes of acute pancreatitis, the backbone of treatment is supportive care, including enteral restriction, aggressive hydration, and pain control. Triglyceride levels may be reduced with lipid-lowering therapy when the patient is able to tolerate oral medication. Intravenous insulin with or without heparin is effective in expediting the reduction of triglyceride levels. Apheresis has been shown to rapidly lower triglyceride levels, but not to reduce complications or mortality associated with acute pancreatitis.13-16

Conclusions

To the authors’ knowledge, this is the first reported case of everolimus-induced hypertriglyceridemia resulting in acute pancreatitis. pNETs themselves can rarely lead to acute pancreatitis.17 However, in this patient, the severely elevated triglyceride level implicates everolimus-induced hypertriglyceridemia as the likely cause. Hypertriglyceridemia is a common side effect of everolimus, and elevation in triglyceride levels, especially greater than 1000 mg/dL, can precipitate acute pancreatitis. With expanding indications for everolimus use, prescribing oncologists must be cognizant of the common and serious side effects. Triglyceride levels should be monitored regularly, and lipid-lowering therapy or a dose-reduction of everolimus, or both, can be considered so that use of the drug can continue in the setting of hypertriglyceridemia.

The authors (Somasundaram Subramaniam, MD; Jason A. Zell, DO; and Pamela L. Kunz, MD) have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer Network.

Ms. Green has disclosed that she has no relevant financial relationships.

CE AUTHOR

Nicole B. Fair, BS, Manager, Continuing Education and Grants

Ms. Fair has disclosed that she has no relevant financial relationships.

Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations

Ms. Gregory has disclosed that she has no relevant financial relationships.

References

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Correspondence: Pamela L. Kunz, MD, Division of Oncology, Stanford University School of Medicine, Stanford Cancer Institute, 875 Blake Wilbur Drive, MC 5826, Stanford, CA 94305. E-mail: pkunz@stanford.edu

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