Lenvatinib is a tyrosine kinase inhibitor that is being used to treat neuroendocrine tumors based on the success shown in the TALENT trial. There are two documented cases of lenvatinib-induced pancreatitis in patients being treated for thyroid cancer. This report describes the first case of pancreatitis seen in a patient with a metastatic neuroendocrine tumor being treated with lenvatinib. A 68-year-old female presented with a chief complaint of epigastric abdominal pain, nausea, and vomiting. She started on lenvatinib therapy 3 months prior to presentation and discontinued the drug 1 week prior due to worsening symptoms. This patient presented with epigastric pain radiating to the back, CT imaging findings consistent with acute pancreatitis, but only a lipase of 88. Once the diagnosis of pancreatitis was made, treatment was initiated with IV fluids, holding all oral intake and pain management. The patient was discharged after she tolerated oral intake after 5 days of hospitalization. It was concluded that the pancreatitis was likely caused by lenvatinib as other etiologies of acute pancreatitis including gallstones, alcohol use, hypertriglyceridemia, and hypercalcemia were ruled out. Clinicians who are using lenvatinib to treat neuroendocrine tumors should be aware of the occurrence of pancreatitis and may consider periodic monitoring for signs and symptoms of pancreatitis. More research regarding the mechanism and development of lenvatinib-induced pancreatitis may benefit clinical decision-making in patients being considered for lenvatinib therapy. Additionally, this therapy may need to be monitored closely in patients with a history of pancreatitis.

© 2023 The Author(s). Published by S. Karger AG, Basel

Lenvatinib is an antineoplastic agent that has been emerging as a common drug of choice to prevent tumor progression in hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer. It belongs to a class of drugs called quinoline carboxiamides [1]. The mechanism of action for this drug is a multi-tyrosine-kinase inhibitor with additional activity as an inhibitor of endothelial growth factor receptors (VEGFR 1–3) and fibroblast growth receptors (FGFR 1–4). It also has activity against platelet-derived growth factor receptors along with disruption of RET oncogene activity. These actions interfere with the microenvironment surrounding the tumor by interrupting tumor assembly and maturation [2]. Trials have shown that lenvatinib has beneficial anti-tumor activity and has reduced time to progression in hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer [1]. Of significance, the TALENT phase II cohort trial completed in 2021 studied the use of lenvatinib in treating gastroenteropancreatic neuroendocrine tumors which are known to be resistant to other systemic chemotherapies. The trial showed that lenvatinib had meaningful benefit in patients with gastroenteropancreatic neuroendocrine tumors that are advanced and have been already pretreated [3]. The most common side effects that patients normally experience are diarrhea, nausea, thrombocytopenia, hypertension, proteinuria, weakness [4]. There are only two reported cases, published by Kim et al. (2020) and Kawakami et al. (2018), regarding lenvatinib-induced acute pancreatitis, both of which occurred in patients being treated for thyroid cancer [5, 6]. Here, we describe a case of a patient who was being treated with lenvatinib for neuroendocrine tumor and subsequently developed acute pancreatitis.

A 68-year-old African American female with a history of neuroendocrine tumor with metastases to the liver presented to our service in April of 2022 for epigastric abdominal pain. Other past medical history includes noninsulin-dependent type 2 diabetes, hypertension, hypothyroidism, vertigo, and GERD. The patient had been diagnosed with a small intestine neuroendocrine tumor (pTa4, N1, M1) in November of 2019 after presenting with a symptomatic small bowel obstruction. At that time, CT imaging showed evidence of a 4.2 cm mass in the lateral segment of the left lobe of the liver as shown in Figure 1. She subsequently underwent exploratory laparotomy for a small bowel resection and liver biopsy. Pathology demonstrated a 2 cm well-differentiated, grade 3, Ki67 30% small-bowel NET involving the jejunum/ileum and visceral peritoneum. PET-Ga 68 showed multiple areas of somatostatin receptor expression throughout the liver consistent with metastasis, confirmed by core needle biopsy of the liver. The patient was subsequently started on 120 mg lanreotide SC which she tolerated well over the next few months. She underwent Y-90 [yttrium-90 radioembolization] to the lateral segment of left lobe in July 2020. Restaging MRI in September 2020 showed disease progression and enhancing metastases. Peptide receptor radionuclide therapy was started in December 2020 of which she received 2 treatments. In March of 2021, scans showed continuing progression of disease and radiation treatment was stopped. She was then started on the CABINET trial using cabozantinib. Restaging scans in December 2021 showed progressing disease after which she was started on lenvatinib in January at an initial dose of 14 mg per day and this was increased to 24 mg per day. The patient endorsed having mild abdominal pain, nausea, and vomiting since starting lenvatinib. These symptoms gradually worsened throughout February and March of 2022, and the patient subsequently self-discontinued the drug 1 week prior to presentation in April 2022 due to these symptoms.

CT abdomen/pelvis with contrast in November of 2019 shows 4.2 cm mass in the lateral segment of the left lobe of the liver.

On admission, her chief complaint was epigastric abdominal pain, nausea, and multiple episodes of vomiting. The abdominal pain was sharp, 10/10, radiated to her back, and worsened with oral intake. She endorsed overall decreased PO intake and mild shortness of breath over the past few months but denied any chest pain, diarrhea, constipation, or dizziness. Her current medication list included amlodipine, metoprolol tartrate, levothyroxine, omeprazole, and pregabalin. On presentation, she was afebrile with a heart rate of 121 bpm, respiratory rate of 18, and blood pressure was 106/73. Physical exam showed an elderly female who was in mild distress due to pain. Heart rate was fast but regular; lungs were clear to auscultation bilaterally. Abdomen was soft, nondistended, but tender to palpation in the epigastric region without rebound tenderness. Bowel sounds were present in all 4 quadrants. Complete blood count showed a hemoglobin of 11 g/dL (reference range, 12–16 g/dL) consistent with the patient’s baseline, no leukocytosis with white blood cell count of 9.3 x109/L (reference range, 4.4–11.3 x109/L). Complete metabolic panel showed a creatinine level of 1.52 mg/dL (reference range, 0.50–1.05 mg/dL), elevated from the patient’s baseline of 1.3 mg/dL. Aspartate aminotransferase was 21 U/L (reference range, 9–39 U/L), alanine transaminase was 10 U/L (reference range, 7–45 U/L), total bilirubin was 0.5 mg/dL (reference range, 0–1.2 mg/dL), alkaline phosphatase was 272 U/L (reference range, 33–136 U/L), albumin was 3.9 g/dL (reference range, 3.4–5.4 g/dL), calcium was 8.8 mg/dL (reference range, 8.6–10.3 mg/dL), corrected calcium was 8.9 mg/dL (reference range, 8.6–10.3 mg/dL). Lactate was 1.6 mmol/L (reference range, 0.4–2.0 mmol/L), troponin was 0.02 ng/mL (reference range, 0–0.03 ng/mL), lipase was very mildly elevated at 88 U/L (reference range, 9–82 U/L). CT abdomen/pelvis showed an enlarged and edematous pancreas with infiltration into the surrounding fat consistent with acute pancreatitis as shown in Figure 2. Despite lipase levels not being elevated, she met criteria for acute pancreatitis according to the Revised Atlanta Criteria with epigastric abdominal pain radiating to the back and CT imaging showing concerns for acute pancreatitis [7].

CT abdomen/pelvis with contrast in April 2022 shows an enlarged and edematous pancreas with infiltration into the surrounding fat consistent with acute pancreatitis.

Our team obtained further tests to look for possible etiologies of pancreatitis. Right upper quadrant ultrasound was unremarkable and with no evidence of gallstones or biliary duct dilation. A lipid panel showed triglyceride level of 198 mg/dL (reference range, 0–149 mg/dL), significantly lower than the level typically associated with causing pancreatitis. Triglyceride levels >1,000 are normally shown to be an identifiable risk factor for pancreatitis [8]. Additionally, the patient denies any history of alcohol use in the past. Serum calcium levels were within normal limits, and there were no drugs on the patient’s medication list that are commonly or atypically associated with causing pancreatitis. Additionally, the patient denied any history of trauma over the past few months. Given the development of acute pancreatitis for the first time following initiation of lenvatinib therapy and no other causes were identifiable, it was concluded that this was likely lenvatinib-induced pancreatitis.

The patient was treated with supportive therapy including IV fluid hydration, holding all oral intake for 5 days (i.e., NPO status) along with nausea and pain control. She clinically improved over the course of 5 days after which she was able to tolerate a full liquid diet. She was discharged in stable condition and she refused to continue on lenvatinib therapy. Patient was scheduled to follow-up with her oncologist 1 week after discharge.

Based on literature review, it appears that this is the first case of lenvatinib-induced pancreatitis in a patient being treated for a neuroendocrine tumor. Of significance, there have been two other case reports which document lenvatinib-associated pancreatitis both of which occurred in patients being treated for thyroid cancer. Our case report is beneficial as it reaffirms the suspicion behind lenvatinib-induced pancreatitis along with redemonstrating certain signs, symptoms, diagnostic process, and treatment course of a patient that encounters this phenomenon. This report also demonstrates that this incidence can occur across patients being treated with this drug regardless of the type of cancer that they may have. Given the fact that more patients with neuroendocrine tumors will be started on lenvatinib therapy following the success rate shown on the 2021 phase 2 trial published by Capdevila et al., it will be more important for side effects to be monitored including the development of acute pancreatitis.

The mechanism of how lenvatinib may induce an episode of acute pancreatitis remains to be unclear. A meta-analysis completed by Ghatalia et al. did demonstrate that there was an elevated relative risk of pancreatitis in patients receiving tyrosine-kinase inhibitor therapy. This analysis studied drugs other than lenvatinib, including sorafenib, pazopanib, axitinib, cabozantinib, and ponatinib among others [9]. Increases in pancreatic enzymes including serum amylase and lipase have been seen in patients being treated with these drugs, particularly sorafenib [10]. It is possible that lenvatinib may be associated with increased release of pancreatic enzymes similar to other tyrosine-kinase inhibitors; however, more research and analysis will be needed in order to determine this.

When our case is compared to the case of lenvatinib-induced pancreatitis published by Kim et al., both had lipase levels that did not meet the typical cutoff for acute pancreatitis, i.e., three times the upper limit of normal. In that particular case, this enzyme level was checked within 1 month of initiation of lenvatinib, whereas with our case the lipase level was checked roughly 3 months after initiation of therapy. This may suggest a pattern that pancreatitis induced by lenvatinib initially may not be associated with significantly elevated pancreatic enzyme levels. However, in the case published by Hawakami et al., their patient had an elevation of lipase level of 924. It is important to note that this laboratory value was checked after 19 months of being on lenvatinib therapy. Looking at this information, it may be reasonable to suggest that lenvatinib therapy may cause elevation in lipase levels over the course of time, even if it is not acutely elevated after initiation of therapy. In a retrospective analysis completed by Balmelli et al. [11] looking at the efficacy of lenvatinib in patients with refractory thyroid cancer, there appears to be one documented case of acute pancreatitis among many other side effects; however, there is no clinical course or presentation that was recorded. Kurokawa et al. completed a single-center retrospective analysis intending to look at computed tomography findings of pancreatobiliary inflammation in patients treated with lenvatinib. They documented 7 cases of recorded cholecystitis, 2 cases of cholangitis, and 1 case of pancreatitis. The patient with pancreatitis was being treated with lenvatinib for hepatocellular carcinoma and had been taking the medication for 11 weeks prior to having abdominal pain. The patient had a similar timeframe of symptoms compared to our patient, however did have imaging findings consistent with acalculous cholecystitis in addition to fat stranding surrounding the pancreas [12]. This may suggest that patients with lenvatinib-induced pancreatitis may be susceptible to other complications such as cholecystitis; however, more information would be needed to make this conclusion. Overall, more data from cancer patients being treated with lenvatinib therapy, including serum amylase and lipase levels, may be beneficial in further understanding the progression of pancreatitis induced by this medication.

In conclusion, acute pancreatitis should be considered as a possible side effect in patients being treated with lenvatinib. A provider may consider monitoring serum lipase levels along with signs and symptoms of pancreatitis on a regular basis. Additionally, providers may also consider exercising caution with initiating this therapy in those with a higher risk of developing pancreatitis, including those with chronic alcohol use, triglyceridemia, and gallstone pathology. More data and analysis regarding this matter would be beneficial in determining the mechanism of this phenomenon along with the progression of pancreatitis seen in these patients. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material at www.karger.com/doi/10.1159/000529730.

Written informed consent was obtained from the patient for publication of the details of their medical case and accompanying images. Ethical approval is not required for this study in accordance with local and national guidelines.

The authors have no conflicts of interest to declare.

No funding was received for this study.

I.A. and S.B. have both individually contributed in the development of the introduction, case report, discussion, and conclusion in this article. Both authors have drafted the article or revised it critically for important intellectual content and have approved for this version to be published.

All data generated or analyzed during this study are included in this article and its online supplementary materials. Further inquiries can be directed to the corresponding author.

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