Pancreatitis associated with newer classes of antineoplastic therapies

Molecularly targeted agents, including TKIs

Molecularly targeted agents such as tyrosine kinase inhibitors (TKIs) or other kinase inhibitors have been associated with pancreatitis.^{17, 18} In a retrospective study by Tiruman and colleagues,¹⁹ the investigators found 91 patients with pancreatitis on imaging, of whom 15 were receiving molecularly target drugs. The pancreatitis was asymptomatic in 2 patients, but 13 had abdominal pain, many with nausea. Four of the patients also had gallstones, but the drug was deemed to be the cause of the pancreatitis. In 4 of the 9 patients in whom a rechallenge was done with the TKI, the pancreatitis relapsed. The pancreatitis resolved in 14 of the 15 patients; 1 patient died because of progressive cancer before the pancreatitis resolved. The pancreatitis was mild, 7 of the 15 patients had normal pancreatic enzymes and the pancreatitis was diagnosed by radiology.

Ghatlia and colleagues¹⁷ performed a meta-analysis of trials of TKI. They found 9 cases of pancreatitis in patients on sunitinib therapy. Of those, 4 patients were on sunitinib alone, and 5 were on other chemotherapy agents in combination with sunitinib. Eight cases of pancreatitis due to sorafenib were found. Three of the patients were on sorafenib alone, and 5 were on other chemotherapy including 1 on transcatheter embolization (TACE). Three cases of pancreatitis were associated with vandetanib; 2 of those patients had other concurrent chemotherapy. One case of axitinib induced pancreatitis was described.

Pancreatitis was reported in the phase 1 trials of sorafenib and sunitinib. In all, 3 of 69 patients treated with sorafenib had grade 3 pancreatitis and asymptomatic elevations of amylase and lipase levels were present in about 5% of patients receiving sunitinib.^18,19

Other TKIs associated with pancreatitis include pazopanib,^20,21 axitinib,²² and nilotinib.²³ Pezzilli and coleagues²⁴ described 5 patients with pancreatitis on sorafenib, 3 on sunitinib, 6 on nilotinib. It is possible that some of these cases appeared in other reviews. Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, caused a single case of pancreatitis in 9 patients.²⁵

Vemurafenib, a BRAF kinase inhibitor, was associated with pancreatitis in one case. In this case, the pancreatitis resolved on stopping the medication but recurred when vemurafenib rechallenge was attempted.²⁶ There is a report of dabrafenib being associated with pancreatitis in 1 patient.²⁷

Agents that inhibit the TKIs associated with BCR-ABL in chronic myelogenous leukemia are associated with acute pancreatitis. Imatinib-induced pancreatitis was reported in a small number of cases.²⁸ Nilotinib has caused amylase/lipase elevations with and without symptomatic pancreatitis.^29,30 Ponatinib, an inhibitor of BCR-ABL tyrosine kinase, is associated with pancreatitis.³¹ Pancreatitis occurred in 11 of 81 patients treated with ponatinib, and in 8 patients it was described as serious. Further elevation of amylase or lipase levels without clinical pancreatitis was noted in 7 other patients.

Proteosome inhibitors

In 2010, Elouni and colleagues³² reported a case of IV bortezomib-induced pancreatitis, which recurred on rechallenge with bortezomib. This same patient was also reported in an abstract in 2009.³³ In 2009, there was an editorial comment which was added to the end of the abstract that the World Health Organization Adverse Drug Reaction database had 11 reports of bortezomib associated pancreatitis. Talamo and colleagues³⁴ reported a case of bortezomib-induced pancreatitis due to bortezomib that had been administered subcutaneously. At that time, they also summarized 7 previous reports of bortezomib-associated pancreatitis. The mechanism of bortezomib-induced pancreatitis is not known.^35-37

Fotoh and colleagues reported a patient with myeloma who had elevated triglyceride levels after bortezomib therapy.³⁸ In one case of bortezomib-associated pancreatitis, the patient had an elevated triglyceride level, but it was not extremely high.³⁹ Multiple myeloma itself may be associated with hyperlipidemia but only rarely.⁴⁰ Gozetti and colleagues reported a patient who developed hyperlipidemia after two courses of bortezomib;⁴¹ stopping bisphosphonates may be associated with a rise in triglycerides. There was one case of carfilzomib causing pancreatitis during a phase 1 trial.⁴²

Older chemotherapy agents

Reviews of drug-induced pancreatitis have listed many chemotherapy agents which may cause pancreatitis.^1,43 The agent most frequently associated with acute pancreatitis has been asparaginase,⁴⁴ with 2%-16% of patients undergoing asparaginase therapy developing pancreatitis. Asparaginase-related pancreatitis is grade 3 or 4 in 5%-10% of patients, and recurs in 63% of patients on rechallenge. Other chemotherapy agents associated with pancreatitis include: mercaptopurine, cytosine arabinoside, cisplatin, interferon alfa-2b, doxorubicin, tamoxifen, gefitinib, vinorelbine, oxaliplatin, levamisole, methotrexate, azathioprine, 5-fluorouracil, capecitabine, ifosfamide, paclitaxel, and all-trans retinoic acid.

Oxaliplatin carries a 0.1%-2% incidence of drug-induced pancreatitis. In one series of 6 patients, cessation of the agent allowed for resolution of symptoms and decrease in serum lipase and amylase levels.⁴⁵ With capecitabine there are 2 case reports of pancreatitis.⁴⁶ Cases of pancreatitis associated with trifluridine or tipiracil were not present in the literature.

Thalidomide caused severe pancreatitis in a patient when it was used to treat chronic graft-versus-host disease.⁴⁷ This patient suffered recurrent pancreatitis on retreatment with the thalidomide. The authors further referenced two other suspected cases of thalidomide-induced, acute pancreatitis. However, in view of the extensive use of thalidomide for multiple myeloma before the development of lenalidomide, thalidomide-associated pancreatitis would be <1% of patients.

Agents that cause hypertriglyceridemia may cause pancreatitis. This mechanism has been reported as the cause of pancreatitis for everolimus⁴⁸ and tamoxifen.^49,50-52 Everolimus causes elevated triglycerides in 30%-50% of patients. There are case reports and a review of tamoxifen-associated pancreatitis caused by elevated triglycerides.⁵² There has also been a case of temsirolimus-associated pancreatitis,⁵³ another agent that elevates triglycerides.