The Journal of Emergency Medicine, Vol 15, No 5, pp 645-647, 1997

Copyright 0 1997 Elsevier Science Inc.

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Selected Topics;
Toxicology

ACUTE PANCREATITIS SECONDARY TO IFOSFAMIDE

Raquel Gerson, MD,* Albert0 Serrano, M&t Albert0 Villalobos, MD,t George L. Sternbach, MD, FACEP,*
and Joseph Varon, MD, FACA, FACP, FCCP§
l Unidad de Quimioterapia, Hospital General de Mexico, and Departamento de Oncologia, The American British Cowdray Hospital,
Mexico City, Mexico; tDepartmento de Medicina Interna, The American British Cowdray Hospital, Mexico City, Mexico; SDepat-tment
of Emergency Medicine, Stanford University Medical Center, Stanford, California: and $Department of Anesthesiology and Critical
Care, M. D. Anderson Cancer Center, Houston, Texas
Reprint Address: Raquel Gerson, MD, Virreyes 1560, Mexico City, 11000, Mexico

[III Abstract-Acute paucreatitis in cancer patients can be
secondary to the malignant process itself. It is also a rare
complication of autineoplastic agent administration. Ifos-
famide is an effective drug in the treatment of several
tumors and has known neurologic, renal, and hematologic
toxicities. There is only one recent report in the literature of
pancreatitis associated with ifosfamide. We report a caseof
a 65year-old woman with small cell bronchogenic carci-
noma without pancreatic metastases who developed acute
pancreatitis after ifosfamide administration. 0 1997
Elsevier Science Inc.
0 Keywords-ifosfamide; pancreatitis; chemotherapy
INTRODUCTION
arabinose all have been reported to induce pancreatitis
(6-14).
Ifosfamide has proven to be an effective drug in the
treatment of osteogenic sarcoma, testicular cancer, lym-
phoma, soft tissue sarcoma, and small cell lung cancer.
With the use of mesna as uroprotector in the prevention of
hemorrhagic cystitis, its application and utilized doses have
been increased (10-12). Although important side effects
are associated with its use, including myelosuppression,
nephrotoxicity, and neurotoxicity (lo- 12), only one case of
pancreatitis has been reported with its use; this in an ado-
lescent girl with osteogenic sarcoma (10). We report a
second case of ifosfamide-induced acute pancreatitis that
presented to the emergency department.

Acute pancreatitis is the result of diverse etiologies, most CASE REPORT

commonly from alcoholism and gallstones (1). In cancer
patients, pancreatitis may be secondary to primary or met-
astatic tumor obstructing the pancreatic ducts. Such meta-
static malignancies from the lung, breast, and stomach are
the most common (2,3). In lung cancer patients, pancreatic
metastases are found in approximately 10% of postmortem
examination cases, three-quarters of these being small cell
carcinoma (2). Pancreatitis in cancer patients also can be
caused by an invasive diagnostic or therapeutic procedure
or by the utilization of cytotoxic drugs (4,5). Azathioprine,
6-mercaptopurine, cisplatin, vinblastine, cyclophospha-
mide, doxorubicin, L-asparaginase,vincristine, and cytosine
A 65year-old woman diagnosed with small cell lung can-
cer me&static to the right adrenal and Central nervous sys-
tem was treated with radiotherapy to the brain simulta-
neously with chemotherapy utilizing VP-16, cisplatin, and
cyclophosphamide. As antiemetics, the patient received on-
dansetron, dexamethasone, lorazepam, and diphenhydra-
mine. Three cycles were administered, and a good response
was obtained, but due to neurotoxicity, cisplatin was re-
placed with carboplatin, with the patient receiving a total of
8 cycles, after which there was remission.
Six months later, chemotherapy was reinstated because

Toxicology is coordinated by Kenneth Kulig, MD, of Toxicology Associates,Denver, Colorado

RECEIVED: 16 September 1996; ACCEPTED: 16 December 1996

645
646
of signsof progressionin the lung and adrenalgland.It was
plannedthat the patientwould receiveifosfamide, 1.2g/m*/
day for 3 days, plus mesna-etoposide100mg/mz/dayfor
l-3 days,and carboplatin300 mg/day/liter. The antiemetic
medication administeredconsistedof the sameagentspre-
viously utilized. Twenty-four hours afterthe seconddoseof
ifosfamide, the patient developed a nonprutitic petechial
rash localized to the abdomenand lower extremities. The
third ifosfamidedosewas omitted.Twenty-four hours after
completingchemotherapyand48 h after the last ifosfamide
dose was administered,she presentedto the emergency
departmentwith severeepigastricpain associatedwith nau-
sea and vomiting. She had not taken other medication or
alcohol, and she had no history of abdominal pain or pre-
vious pancreatitis.The patient’s physical examination re-
vealedmarkedepigastrictenderness,no reboundtenderness
nor liver enlargement,and decreasedbowel sounds.Labo-
ratory testsshoweda white blood cell count of 10,500/mm3
(increasedfrom 7,900/mm3at the initiation of treatment)
and hemoglobin of 10.8gBL. Serum amylase was 452
U/liter (normal, 25-125 U/liter) and lipase402 U/liter (nor-
mal, O-19 U/liter); glucosewas 158 mg/dL. The remainder
of the laboratoryevaluationwas within the normal range.A
computed tomography scan of the abdomen revealed a
normal biliary systemand normal pancreaswith no tumor
or hepatic metastases.The patient was admitted to the
hospital and treatedconservativelywith intravenousfluids,
analgesics,and no oral intake. After 6 days, the symptoms
subsidedand laboratory results revertedto normal.
Readministrationof ifosfamide was refusedby the pa-
tient and her family, and she was not rechallengedwith it.
Subsequently,she received paclitaxel with no response.
Cerebral me&stasesreappearedand she was placed on
corticosteroids.Oral VP-16 was tried with no efficacy.The
patient did not redevelopany abdominalcomplication, and
expired 5 months after the episodeof pancreatitis.
DISCUSSION
The patient developedacute pancreatitiswith severeepi-
gastric pain, nauseaand vomiting, and elevated amylase
and lipase 2 days after ifosfamideadministration.No other
medicationsknown to provoke pancreatitishad been ad-
ministered.The antiemeticschemewasthe sameaswith the
previously administered eight cycles, no corticosteroids
were taken, and shehad no history of biliary disease.In an
extensive review of acute pancreatitis,Frick et al. found
most casesto be associatedwith underlying conditions
known to induce acutepancreatitis,suchashyperlipidemia,
pregnancy,hypercalcemia,Crohn’s disease,or tumor in-
volvement,all of which were excludedin this patient (15).
Acute pancreatitishas been describedin associationwith
severalantineoplasticagents,including L-asparaginase, aza-
R. Gerson et al.
thioprine, 6-mercaptopurine,and vincu alkaloids. Experi-
mentally, vincu alkaloids have induced severepancreatic
ultrastructuraldamagein mice (15,16).Pancreatitishasalso
been describedin combination chemotherapywith 5-flu-
orouracil, vincristine, methotrexate,mitomycin-C, and cy-
clophosphamideas well as doxorubicin, cyclophospha-
mide, and vincristine. (6,8,9,15,16) It also has been
attributed to ondansetron,due to its decreasedpancreatic
secretoryactivity or to a hypersensitivityreaction.(17) Our
patient had received ondansetronon severaloccasionsbut
without any such effect. The physiologic mechanismthat
generatesacute pancreatitiswith azathioprineand 6-mer-
captopurineis thought to involve an immunologic response
with antibody formation. This responsecan activateT cells
in vitro and results in tissue damagethat is probably T
lymphocyte mediated. (9) Although it is presumedthat
pancreatitis induced by other agentsis also an immune-
mediatedinflammatoryresponse,drug-inducedpancreatitis
is usually not associatedwith common allergic reactions
such as urticaria and doesnot usually occur in individuals
with a background of allergic disorders.(16) The use of
cytotoxic agentsthrough arterial hepaticperfusion and via
intraperitonealinstillation hasbeendescribedto causepan-
creatitis. (4,5) Acute pancreatitisin nonpancreaticcancer
patientscan be the result of causesassociatedwith under-
lying conditions or secondaryto drug side effects,hyper-
calcemia,or pancreaticmetastases.Such metastaseshave
beenreportedin breast,prostate,andrenal cancers,andless
frequently, melanoma,carcinomaof the tonsils, and hepa-
toma. (2,3)
There has been one case described of acute pancre-
atitis causedby ifosfamide. This was a 16-year-old girl
with osteogenic sarcomawho developed severe abdom-
inal pain, vomiting, and amylase and lipase elevation
24 h after the final ifosfamide dose.(10) The patient was
rechallengedwith the drug on two subsequentoccasions,
and the sameclinical picture recurred. The dosesutilized
varied from 900 mg/m2/dayfor 3 days to 1800 and 1200
again in 3 days. Our patient developed the full-blown
symptomatology of pancreatitis 2 days after the last dose
of ifosfamide. The dose schemewas similar to the one
described by Izraeli et al., although the last day’s dose
was not given (10). Drug-induced pancreatitis has been
found to have a high variability with respectto the dose
administered and the interval between drug intake and
the onset of acute symptoms. (15)
CONCLUSIONS
Pancreatitis is a rare complication of ifosfamide admin-
istration. This entity should be considered in cancer
patients with the pertinent clinical presentation.
Pancreatitis and lfosfamide
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