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Gemcitabine-associated hemolytic-uremic syndrome
CASE REPORT
Gemcitabine-Associated Hemolytic-Uremic Syndrome Roland B. Walter, MD, Markus Joerger, MD, and Bernhard C. Pestalozzi, MD ● Background: Gemcitabine has mild renal toxicity, but cases of gemcitabine-associated hemolytic-uremic syndrome (HUS) have been reported. Methods: A case is presented of a 45-year-old woman on prolonged gemcitabine treatment for ovarian cancer who developed HUS and recovered after drug discontinuation. A mini-review of the literature based on a MEDLINE search follows. Results: Including our own patient, a total of 26 cases of gemcitabine-associated HUS were identified. Median patient age was 52 years. Treatment was for various tumors at advanced stages, and in some patients, other anticancer drugs previously had been administered. Mean time between initiation of gemcitabine therapy and onset of HUS was 7.4 ⴞ 3.5 months, or 21.9 ⴞ 10.9 doses of gemcitabine. The calculated median cumulative dose of gemcitabine was 20,000 mg/m2 (range, 2,450 to 48,000 mg/m2, or a total of 70,000 mg). The onset of disease was noted up to 2 months after the last gemcitabine infusion. Diagnosis of HUS was confirmed histologically in 13 patients and based on clinical findings in the other 15. Treatment included drug discontinuation, steroids, fresh frozen plasma, hemodialysis, absorption chromatography, plasmapheresis, and various combinations thereof. Of 23 patients with reported outcome, 11 died within a few weeks. In two cases, death was believed to be a direct consequence of HUS. Reexposure to the drug was reported in three patients but was uncomplicated in only one. Conclusion: There are only a few confirmed cases of gemcitabineassociated HUS despite the widespread use of the drug. This potentially fatal complication is difficult to treat and should be widely known. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Acute uremia; chemotherapy; gemcitabine; hemolytic-uremic syndrome (HUS); microangiopathic hemolytic anemia; renal failure; thrombocytopenia; thrombotic microangiopathy.
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EMCITABINE (2⬘,2⬘-difluorodeoxycytidine) is a difluorinated analogue of deoxycytidine. The first phase I clinical and pharmacologic studies were reported in 1991 and 1992. Because of its significant activity against several human solid tumors in preclinical studies and clinical phase II trials, the drug rapidly moved into phase III studies. Preclinical studies indicated that toxicity with gemcitabine was likely to be schedule dependent. Subsequently a weekly schedule for 3 weeks followed by 1 week of rest provided efficacy with minimal toxicity and boosted widespread use of the drug in singledrug schemes (typically at a dose of 1,000 mg/m2/ wk) but mostly in combination with other established anticancer agents, such as cisplatin or 5-fluorouracil.1 The drug’s safety profile repeatedly has been confirmed, with mild, short-lived myelosuppression and little associated infection or hemorrhage, reversible elevations in liver function tests without evidence of cumulative hepatotoxicity, peripheral edema formation, transient flulike symptoms, rare mucositis and alopecia, and mild nausea and vomiting as the most important adverse events.2-5 Although mild changes of urinalysis (proteinuria and microscopic hematuria) were reported frequently in phase II trials with single-agent
gemcitabine, they were rarely of clinical significance. World Health Organization (WHO) grade 1 and 2 proteinuria and microscopic hematuria developed in 58% and 41% of patients and 17% and 8% of patients showed WHO grade 1 or 2 elevations in blood urea nitrogen and creatinine levels.4 Nevertheless, some cases of renal failure of uncertain cause were recorded, and in a phase II trial of patients with pancreatic cancer in 1994, Casper et al6 were the first to report the association of gemcitabine therapy and hemolyticuremic syndrome (HUS). This microangiopathic disorder currently is believed to result from injury to endothelial cells, loss of their antithrombogenic properties, and release of ultralarge von Willebrand factor multimers leading to vessel wall thickening, intraluminal platelet thromboFrom the Medical Clinic B and Division of Oncology, Department of Internal Medicine, University Hospital, Zu¨rich, Switzerland. Received April 17, 2002; accepted in revised form June 17, 2002. Address reprint requests to Roland B. Walter, MD, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D2-373, Seattle, WA 98109-1024. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 1523-6838/02/4004-0030$35.00/0 doi:10.1053/ajkd.2002.35758
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sis, and partial or complete obstruction of the vessel lumina. Clinically, HUS is characterized by the triad of microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia.7 Since 1994, occasional cases of HUS that followed chemotherapy with gemcitabine have been reported, and a crude overall incidence rate of 0.015% has been determined based on the manufacturer’s worldwide pharmacovigilance and epidemiology safety database.8 We present a case of HUS after prolonged treatment with gemcitabine for ovarian cancer. We also review the literature about this potentially fatal adverse event. CASE REPORT A 45-year-old woman was diagnosed with moderately differentiated adenocarcinoma of the ovary, FIGO IIIC stage, in November 1998. The patient underwent cytoreductive surgery with suboptimal resection. First-line chemotherapy with cisplatin/paclitaxel resulted in no tumor response. Second-line therapy with topotecan could not prevent radiologically documented tumor progression. After a short trial with tamoxifen, chemotherapy with carboplatin/paclitaxel was initiated, but the tumor progressed again. In July 1999, chemotherapy with weekly gemcitabine, 1,000 mg/m2, was begun.9,10 Gemcitabine was well tolerated, although several doses had to be omitted because of a low platelet count. Paracentesis was necessary for recurrent ascites. The tumor marker CA-125 decreased from 360 IE/mL (normal range, ⬍30 IE/mL) in July 1999 to 115 IE/mL in January 2000. Although CA-125 subsequently tended to increase, therapy was continued because the disease remained clinically stable. In May 2000, after a total dose of 70 g of gemcitabine, blood transfusions repeatedly were required because of progressive anemia. Subsequently, treatment with gemcitabine was discontinued. The decrease of hemoglobin was accompanied by deteriorating renal function with minimal measured creatinine clearance of 19.8 mL/min (0.33 mL/s), marked proteinuria (3.8 g/24 hours), microhematuria, thrombocytopenia of 69 ⫻ 103/L (69 ⫻ 109/L), increase in serum lactate dehydrogenase (LDH) (1,138 U/L; normal range, 150 to 420 U/L), peripheral edema, pleural effusions, hemorrhagic ascites, arterial hypertension (200/120 mm Hg), and thrombosis of the left internal jugular vein. Based on these features and a peripheral blood smear showing fragmented red blood cells, a diagnosis of microangiopathic hemolytic anemia was made. After discontinuation of gemcitabine therapy, laboratory parameters slowly improved over the next weeks and normalized in November 2000 without specific treatment. In February 2001, tumor progression caused massive ascites and abdominal pain. Because gemcitabine was considered the only effective therapy for this patient, oral informed consent was obtained for reexposure to the drug. Gemcitabine, 1,000 mg/m2, was administered with dexamethasone, 8 mg, in March 2001, and the latter was tapered over the next 2 days. Transient macrohematuria developed on the first day after reexposure to gemcitabine, however, and
persisted for 5 days. Because urinary bleeding initially was ascribed to tumor invasion of the lower urinary tract, a second dose of gemcitabine was administered after resolution of macrohematuria. Two days later, macrohematuria reappeared and was accompanied by slight increases of serum creatinine and LDH and a decrease of the platelet counts. Although no fragmented red blood cells were visible in the peripheral blood smear, chemotherapy with gemcitabine was discontinued because drug-induced renal toxicity was assumed. Subsequently, laboratory parameters returned to normal within the following weeks. No further chemotherapy was given, and the patient died in May 2001 as a result of progressive disease.
METHODS A MEDLINE search up to December 31, 2001, was conducted to identify previous reports of gemcitabineassociated HUS. The search was done by intersecting gemcitabine with acute uremia, hemolysis, hemolytic-uremic syndrome, HUS, microangiopathic hemolytic anemia, (acute) renal failure, thrombocytopenia, and thrombotic microangiopathy. Identified articles were read carefully for references to other articles eventually not found by MEDLINE. Only cases meeting classic clinical or histologic criteria for HUS were included in the review.
RESULTS
Including our own case and considering double and triple publications (one single case described by Brodowicz et al11 and Fung et al8; another case described by Casper et al,6 Flombaum et al,12 and Fung et al8; a third probably identical case reported by Lhotta et al13 and Fung et al8) a total of 26 different cases of HUS associated with gemcitabine were identified in the literature up to December 31, 2001.6,8,11-23 Because of the varying completeness of reporting, findings are not presented in tabular form. The first case of biopsy-proven HUS associated with gemcitabine monotherapy was reported in a phase II trial of patients with pancreatic adenocarcinoma in 1994.6 Another case of HUS was suspected in a patient with small cell lung cancer treated with gemcitabine.24 The possibility of HUS was considered only retrospectively based on clinical and laboratory findings. Shortly thereafter, two patients with metastatic adenocarcinoma of the lung were reported from another phase II trial. They developed acute renal failure 4 and 6 weeks after the last dose of gemcitabine. The diagnosis was confirmed in both cases by histology.25 In a review of the manufacturer’s database containing serious adverse events from clinical trials and spontaneous
GEMCITABINE-ASSOCIATED HUS
reports from postmarketing experience up to December 1997, 12 cases of HUS associated with single-agent gemcitabine were identified. All cases met either clinical (ie, acute uremia, microangiopathic hemolytic anemia, and thrombocytopenia) or histologic criteria (renal biopsy).7 This is the largest series of patients described to date.8 Single cases and small series of patients were reported by several investigators.11-23 Among the 26 cases of gemcitabine-associated HUS, 11 were on clinical trials, and 15 were identified by surveillance. There were 10 women and 12 men and 4 cases with unspecified sex. Median age was 52 years (range, 26 to 73 years; information available for 23 patients). Diagnosis included primary pancreatic (n ⫽ 12), small cell lung (n ⫽ 5), gastric (n ⫽ 1), ovarian (n ⫽ 2), transitional cell (n ⫽ 1), biliary (n ⫽ 1), and duodenal papillary (n ⫽ 1) cancers; hepatic adenocarcinoma with suspected pancreatic or cholangiocellular primary tumor (n ⫽ 1); malignant pleural mesothelioma (n ⫽ 1); and peripheral T cell lymphoma (n ⫽ 1). All tumors were at an advanced stage (23 patients). Prior chemotherapy had been administered to 10 patients: mitomycin-C in 1, 5-fluorouracil in 3, mitomycin/ 5-fluorouracil in 1, cisplatin/bleomycin/etoposide in 1, cyclophosphamide/leucovorin/5-fluorouracil/tamoxifen in 1, and high-dose cyclophosphamide/doxorubicin/vincristine/prednisolone/retinoic acid in 1. One patient had been treated with three different chemotherapy regimens (cyclophosphamide/cisplatin/epirubicin, taxol/carboplatin, and topotecan). As mentioned, our patient had been pretreated with cisplatin/ paclitaxel, topotecan, tamoxifen, and carboplatin/ paclitaxel. For one subject, no data were available about prior chemotherapeutic treatments. In one patient, carboplatin was administered concomitantly with gemcitabine. In another patient, HUS developed after 9 weekly administrations of gemcitabine, which followed a prior combined treatment with locoregional mitomycin C and systemic gemcitabine for seven cycles. One patient was treated with gemcitabine for four cycles for advanced small cell lung cancer. After developing side effects resembling capillary leak syndrome, he was withdrawn from the study, then received one cycle of chemotherapy with carboplatin and vindesine; subsequently, HUS
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developed 5 weeks after initiation of the secondline therapy. Diagnosis of HUS was confirmed by renal biopsy or autopsy in 13 patients. All these patients had laboratory findings of hemolytic anemia, and only two cases lacked fragmented red blood cells on peripheral blood smears. No biopsy was done in 10 patients, but diagnosis was ascertained by features of microangiopathic hemolytic anemia with fragmented red blood cells. In one patient with acute uremia, anemia, transient thrombocytopenia, rising LDH, and low haptoglobin levels, a skin biopsy was done for evaluation of livedo reticularis, revealing focal intravascular fibrin, slight dermal fibrosis, and focal lymphohistiocytic inflammatory cell infiltrates at the dermal-subcutaneous junction suggesting generalized microvascular toxic effects. In two patients, the criteria for diagnosis were not indicated. New-onset thrombocytopenia was noted in 20 of 20 subjects for whom this information was available. New-onset hypertension or exacerbation of underlying hypertension was present in 15 of 21 subjects. Dyspnea, with or without pulmonary edema, was found in 12 of 22 assessed patients. Edema of the ankles or lower legs was described in four patients, ascites in two (with one of them suffering from advanced ovary cancer), pleural effusion in two, pericardial effusion in one, cardiomegaly in one, lung infiltrates in one, self-limiting diarrhea in one, and nonspecific central nervous system symptoms (eg, headache, blurred vision, or confusion) in six. Two subjects presented with livedo reticularis of the legs and had skin ulcers. In both of them, cryoglobulins were found positive or trace positive during the course of illness. The mean duration between initiation of gemcitabine therapy and onset of HUS was 7.4 ⫾ 3.5 months (range, 2.5 to 16 months), corresponding to approximately 21.9 ⫾ 10.9 applications (range, 7 to 48 applications). These are only approximate values, however, because information concerning the duration of treatment and scheduling of gemcitabine was missing in one patient and was limited in others. Similarly, information on the cumulative dose was missing in 1 patient; for 5 patients, only total-milligram doses were noted, whereas for 20, the dose was indicated in mg/m2. For estimation, we assumed the five patients to
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be 1.73 m2. The resulting calculated median cumulative dose was 20,000 mg/m2 (range, 2,450 to 48,000 mg/m2, or a total of 70,000 mg). Although HUS developed during chemotherapy with gemcitabine in some patients, the onset of HUS was noted up to 2 months after the last infusion in others. Gemcitabine was discontinued without the need for further treatment in two patients (our case and another patient who also improved spontaneously). A variety of different treatments were tried in the remaining patients, including fresh frozen plasma without improvement of renal function in one patient, and steroids with at least stabilization of renal function in two patients. In another case, steroids were unsuccessful, and the patient underwent transient hemodialysis with subsequent improvement of renal function. Dialysis was applied to an additional eight patients, and one patient was treated with absorption chromatography. In only two of these patients, an improvement of renal function was noted. In one patient, death was attributed to acute renal failure, and in one patient death was suspected to be due to the consequences of thrombotic microangiopathy. Two patients were treated with plasmapheresis, with one patient recovering almost completely. A third patient was treated successfully with a short course of steroids after a single plasma exchange. A fourth patient temporarily improved after plasmapheresis and steroids but relapsed and remained refractory to further treatment soon thereafter. Dialysis and plasmapheresis were applied in two patients, with one showing an improvement in renal function, whereas the other died as a result of renal failure and further complications. One patient underwent plasmapheresis and splenectomy and received immunoglobulins resulting in improved renal function. Hemolysis resolved in one patient treated with hemodialysis, plasmapheresis, and steroids, but chronic renal failure persisted. Renal function finally improved in one patient treated with fresh frozen plasma, a single hemodialysis session, and plasmapheresis. Treatments and outcome were not reported in two patients. Reexposure to gemcitabine was reported in two additional patients besides our patient. In one patient, the drug was reintroduced several months later because of tumor progression. After the administration of 3,000 mg, the patient was
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noted to “do well without any recurrence of HUS.” In a second patient in whom reintroduction was attempted, an acute myocardial infarction occurred after the second dose, resulting in death. A postmortem examination was not done, but laboratory examinations were not suggestive for recurrent HUS at the time of the cardiac event. DISCUSSION
Mechanisms of chemotherapy-induced renal dysfunction include prerenal perfusion deficits, damage to vessels or other structures of the kidneys, and HUS.26 HUS is a devastating, potentially fatal multisystem process characterized clinically by thrombocytopenia, microangiopathic hemolytic anemia, impaired renal function, and neurologic dysfunction and histologically by thrombotic microangiopathy.7 Its pathophysiology is incompletely understood, but endothelial injury is the central feature and likely inciting factor. Abnormalities in thromboresistance, leukocyte adhesion, complement, von Willebrand factor, and vascular shear stress may sustain and amplify the microangiopathic process.7 It has long been recognized that HUS may occur in cancer patients not receiving chemotherapy,27 and this strongly suggests the presence of disseminated disease.28,29 A growing number of chemotherapeutic agents, principally mitomycin C but also cisplatin and bleomycin, have been linked to the development of HUS. Gemcitabine has no structural similarity to those drugs but is related to cytosine-arabinoside (cytarabine), a drug that so far has been associated with HUS only anecdotally in combination with other chemotherapeutic agents.30,31 The incidence of HUS after treatment with mitomycin C varies from less than 2% to 10 or 15% but is much less common with other chemotherapeutic agents.29,32 The incidence of gemcitabine-associated HUS has been estimated to be 0.008% to 0.078% based on the manufacturer’s database of adverse events.8 It is possible, however, that the reported incidence increases as clinicians become more familiar with this diagnostic possibility. The time interval between chemotherapyinduced damage and the occurrence of HUS is extremely variable. The interval from the last
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dose of gemcitabine to the development of HUS ranged from 1 day to several months.28,29 Mitomycin-induced HUS is related to the cumulative dose.29 Gemcitabine-associated HUS developed after an estimated median cumulative dose of 20,000 mg/m2 with a range from 2,450 mg/m2 to 48,000 mg/m2, or a total of 70,000 mg. With this broad range, the association with the cumulative dose seems less clear-cut for gemcitabine. Because most gemcitabine-treated patients presenting with HUS have far advanced disease and some have received other agents known to be associated with HUS, the exact role of the underlying disease and chemotherapeutic agents is not easily delineated. Although microangiopathy caused by disseminated cancer and chemotherapy-associated HUS may represent two distinct syndromes, and distinguishing clinical and histologic features have been identified for these two conditions,29 there may be more similarities than differences.28 Nevertheless, clinical improvement after gemcitabine withdrawal in some cases and the result from reexposure to the drug in our case strongly suggest gemcitabine to be causative for HUS. It remains speculative whether the acute myocardial infarction that occurred after reexposure to the drug6,8,12 was unrelated to gemcitabine treatment or was due to undetected microvascular changes. Clinically, an individual patient with gemcitabine-associated HUS may present with worsening of anemia, thrombocytopenia, increments of LDH or serum creatinine, elevated blood pressure, dyspnea, peripheral edema, neurologic signs, or hematuria. Accurate diagnosis of the disorder may be delayed because anemia and thrombocytopenia may be attributed to myelotoxicity of the anticancer agent. Although an elevated reticulocyte count may be an important clue to the hyperregenerative hemolytic anemia characterizing HUS,19 it may be low because of prior blood transfusions or myelosuppression.22 When the diagnosis is suspected, peripheral blood smears should be screened for the presence of fragmented red blood cells; these were missing in only a few of the biopsy-proven cases of gemcitabine-associated HUS. Likewise, increased levels of LDH are observed frequently in tumor patients, but a marked increase in LDH should be noted on development of HUS.13 Coagulation tests, including prothrombin time, activated par-
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tial thromboplastin time, and fibrin degradation products, remain normal, in contrast to patients presenting with disseminated intravascular coagulation. Because proteinuria and microscopic hematuria are frequent, it is unlikely that they can serve as an early screening method for impending gemcitabine-associated HUS. By contrast, an unexplained increase in serum creatinine should alert the clinician to this possibility. Today, glucocorticoids and plasma infusion may be used in the initial management, but plasma exchange is the mainstay of treatment.33,34 Nevertheless, chemotherapy-associated HUS remains a highly fatal disease, with a case-fatality rate of 50% to 70%,29,32,35 with early deaths usually related to direct complications of the syndrome.29 In the present review, 11 of 23 patients with reported outcome died within a few weeks after the onset of HUS, and in 2 cases death was believed to be a direct consequence of HUS. In conclusion, there are few confirmed cases of gemcitabine-associated HUS that have been published so far despite the widespread use of the drug. Although it seems rare, this disorder is potentially fatal, and ancillary treatments or antidotes improving outcome have not been identified. A high index of suspicion for HUS is essential when cancer patients are treated with gemcitabine, especially with prolonged therapy. Any worsening of anemia, thrombocytopenia, increments of LDH or serum creatinine, clinical deterioration with elevated blood pressure, dyspnea, peripheral edema, neurologic signs, or hematuria should prompt a careful evaluation and the timely discontinuation of gemcitabine. REFERENCES 1. Chu E, Mota AC, Fogarasi MC: Pharmacology of cancer chemotherapy: Antimetabolites, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 6). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 388-415 2. Aapro MS, Martin C, Hatty S: Gemcitabine—a safety review. Anticancer Drugs 9:191-201, 1998 3. Cortes-Funes H, Martin C, Abratt R, Lund B: Safety profile of gemcitabine, a novel anticancer agent, in nonsmall cell lung cancer. Anticancer Drugs 8:582-587, 1997 4. Green MR: Gemcitabine safety overview. Semin Oncol 23:32-35, 1996 (suppl 10) 5. Tonato M, Mosconi AM, Martin C: Safety profile of gemcitabine. Anticancer Drugs 6:627-632, 1995 (suppl 6) 6. Casper ES, Green MR, Kelsen DP, et al: Phase II trial
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of gemcitabine (2,2⬘-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 12:2934, 1994 7. Ruggenenti P, Noris M, Remuzzi G: Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 60:831-846, 2001 8. Fung MC, Storniolo AM, Nguyen B, Arning M, Brookfield W, Vigil J: A review of hemolytic uremic syndrome in patients treated with gemcitabine therapy. Cancer 85:20232032, 1999 9. Orlando M, Mandachain M: Gemcitabine in ovarian cancer. Semin Oncol 28:62-69, 2001 (suppl 10) 10. Ozols RF: The current role of gemcitabine in ovarian cancer. Semin Oncol 28:18-24, 2001 (suppl 7) 11. Brodowicz T, Breiteneder S, Wiltschke C, Zielinski CC: Gemcitabine-induced hemolytic uremic syndrome: A case report. J Natl Cancer Inst 89:1895-1896, 1997 12. Flombaum CD, Mouradian JA, Casper ES, Erlandson RA, Benedetti F: Thrombotic microangiopathy as a complication of long-term therapy with gemcitabine. Am J Kidney Dis 33:555-562, 1999 13. Lhotta K, Ku¨hr T, Rumpelt HJ, Wo¨ll E, Thaler J, Ko¨nig P: Thrombotic microangiopathy with renal failure in two patients undergoing gemcitabine chemotherapy. Am J Nephrol 19:590-593, 1999 14. Stadler WM, Kuzel T, Roth B, Raghavan D, Dorr FA: Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 15:3394-3398, 1997 15. Nackaerts K, Daenen M, Vansteenkiste J, Vandevelde A, Van Bleyenbergh P, Demedts M: Hemolytic-uremic syndrome caused by gemcitabine. Ann Oncol 9:1355, 1998 16. Berk SH, Schilsky RL: The association of gemcitabine and hemolytic uremic syndrome: A case report. J Invest Med 46:274A, 1998 (suppl S) 17. Choi M, Woywodt A, Go¨bel U, Schneider W, Kettritz R: Haemolytic uraemic syndrome after gemcitabine treatment for pancreatic carcinoma. Nephrol Dial Transplant 14:2523-2524, 1999 18. van Meerbeeck JP, Baas P, Debruyne C, et al: A phase II study of gemcitabine in patients with malignant pleural mesothelioma. Cancer 85:2577-2582, 1999 19. Serke S, Riess H, Oettle H, Huhn D: Elevated reticulocyte count—a clue to the diagnosis of haemolytic-uraemic syndrome (HUS) associated with gemcitabine therapy for metastatic duodenal papillary carcinoma: A case report. Br J Cancer 79:1519-1521, 1999 20. Klapdor R, Seutter E, Lang-Po¨lckow EM, Reichle H, Hinrichs A: Locoregional/systemic chemotherapy of locally advanced/metastasized pancreatic cancer with a combination of mitomycin-C and gemcitabine and simultaneous follow-up by imaging methods and tumor markers. Anticancer Res 19:2459-2469, 1999
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21. Gross M, Hiesse C, Kriaa F, Goldwasser F: Severe hemolytic uremic syndrome in an advanced ovarian cancer patient treated with carboplatin and gemcitabine. Anticancer Drugs 10:533-536, 1999 22. Eckel F, Lersch C, Erdmann J, Schmidt B, SchulteFrohlinde E: 42-ja¨hriger Patient mit ha¨molytisch-ura¨mischem Syndrom unter Gemcitabin-Therapie eines Adenokarzinoms der Leber. Ha¨molytisch-ura¨misches Syndrom und Gemcitabin. Z Gastroenterol 38:593-596, 2000 23. Dumontet C, Morschhauser F, Solal-Celigny P, et al: Gemcitabine as a single agent in the treatment of relapsed or refractory low-grade non-Hodgkin’s lymphoma. Br J Haematol 113:772-778, 2001 24. Abratt RP, Bezwoda WR, Falkson G, Goedhals L, Hacking D, Rugg TA: Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: A phase II study. J Clin Oncol 12:1535-1540, 1994 25. Anderson H, Lund B, Bach F, Thatcher N, Walling J, Hansen HH: Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: A phase II study. J Clin Oncol 12:1821-1826, 1994 26. Kintzel PE: Anticancer drug-induced kidney disorders. Drug Saf 24:19-38, 2001 27. Brain MC, Dacie JV, Hourhaine DO: Microangiopathic haemolytic anaemia: The possible role of vascular lesions in pathogenesis. Br J Haematol 8:358-374, 1962 28. Gordon LI, Kwaan HC: Cancer- and drug-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Semin Hematol 34:140-147, 1997 29. Murgo AJ: Thrombotic microangiopathy in the cancer patient including those induced by chemotherapeutic agents. Semin Hematol 24:161-177, 1987 30. Okumura H, Nakamura S, Ohtake S, et al.: Hemolytic uremic syndrome developing during remission of acute myelomonocytic leukemia. Am J Hematol 44:66-67, 1993 31. Byrnes JJ, Baquerizo H, Gonzalez M, Hensely GT: Thrombotic thrombocytopenic purpura subsequent to acute myelogenous leukemia chemotherapy. Am J Hematol 21:299304, 1986 32. Lesesne JB, Rothschild N, Erickson B, et al: Cancerassociated hemolytic-uremic syndrome: Analysis of 85 cases from a national registry. J Clin Oncol 7:781-789, 1989 33. Kwaan HC, Soff GA: Management of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Semin Hematol 34:159-166, 1997 34. Neild GH: Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura: Pathophysiology and treatment. Kidney Int Suppl 64:S45-S49, 1998 35. Sheldon R, Slaughter D: A syndrome of microangiopathic hemolytic anemia, renal impairment, and pulmonary edema in chemotherapy-treated patients with adenocarcinoma. Cancer 58:1428-1436, 1986
Gemcitabine-Associated Hemolytic-Uremic Syndrome Roland B. Walter, MD, Markus Joerger, MD, and Bernhard C. Pestalozzi, MD ● Background: Gemcitabine has mild renal toxicity, but cases of gemcitabine-associated hemolytic-uremic syndrome (HUS) have been reported. Methods: A case is presented of a 45-year-old woman on prolonged gemcitabine treatment for ovarian cancer who developed HUS and recovered after drug discontinuation. A mini-review of the literature based on a MEDLINE search follows. Results: Including our own patient, a total of 26 cases of gemcitabine-associated HUS were identified. Median patient age was 52 years. Treatment was for various tumors at advanced stages, and in some patients, other anticancer drugs previously had been administered. Mean time between initiation of gemcitabine therapy and onset of HUS was 7.4 ⴞ 3.5 months, or 21.9 ⴞ 10.9 doses of gemcitabine. The calculated median cumulative dose of gemcitabine was 20,000 mg/m2 (range, 2,450 to 48,000 mg/m2, or a total of 70,000 mg). The onset of disease was noted up to 2 months after the last gemcitabine infusion. Diagnosis of HUS was confirmed histologically in 13 patients and based on clinical findings in the other 15. Treatment included drug discontinuation, steroids, fresh frozen plasma, hemodialysis, absorption chromatography, plasmapheresis, and various combinations thereof. Of 23 patients with reported outcome, 11 died within a few weeks. In two cases, death was believed to be a direct consequence of HUS. Reexposure to the drug was reported in three patients but was uncomplicated in only one. Conclusion: There are only a few confirmed cases of gemcitabineassociated HUS despite the widespread use of the drug. This potentially fatal complication is difficult to treat and should be widely known. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Acute uremia; chemotherapy; gemcitabine; hemolytic-uremic syndrome (HUS); microangiopathic hemolytic anemia; renal failure; thrombocytopenia; thrombotic microangiopathy.
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EMCITABINE (2⬘,2⬘-difluorodeoxycytidine) is a difluorinated analogue of deoxycytidine. The first phase I clinical and pharmacologic studies were reported in 1991 and 1992. Because of its significant activity against several human solid tumors in preclinical studies and clinical phase II trials, the drug rapidly moved into phase III studies. Preclinical studies indicated that toxicity with gemcitabine was likely to be schedule dependent. Subsequently a weekly schedule for 3 weeks followed by 1 week of rest provided efficacy with minimal toxicity and boosted widespread use of the drug in singledrug schemes (typically at a dose of 1,000 mg/m2/ wk) but mostly in combination with other established anticancer agents, such as cisplatin or 5-fluorouracil.1 The drug’s safety profile repeatedly has been confirmed, with mild, short-lived myelosuppression and little associated infection or hemorrhage, reversible elevations in liver function tests without evidence of cumulative hepatotoxicity, peripheral edema formation, transient flulike symptoms, rare mucositis and alopecia, and mild nausea and vomiting as the most important adverse events.2-5 Although mild changes of urinalysis (proteinuria and microscopic hematuria) were reported frequently in phase II trials with single-agent
gemcitabine, they were rarely of clinical significance. World Health Organization (WHO) grade 1 and 2 proteinuria and microscopic hematuria developed in 58% and 41% of patients and 17% and 8% of patients showed WHO grade 1 or 2 elevations in blood urea nitrogen and creatinine levels.4 Nevertheless, some cases of renal failure of uncertain cause were recorded, and in a phase II trial of patients with pancreatic cancer in 1994, Casper et al6 were the first to report the association of gemcitabine therapy and hemolyticuremic syndrome (HUS). This microangiopathic disorder currently is believed to result from injury to endothelial cells, loss of their antithrombogenic properties, and release of ultralarge von Willebrand factor multimers leading to vessel wall thickening, intraluminal platelet thromboFrom the Medical Clinic B and Division of Oncology, Department of Internal Medicine, University Hospital, Zu¨rich, Switzerland. Received April 17, 2002; accepted in revised form June 17, 2002. Address reprint requests to Roland B. Walter, MD, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D2-373, Seattle, WA 98109-1024. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 1523-6838/02/4004-0030$35.00/0 doi:10.1053/ajkd.2002.35758
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sis, and partial or complete obstruction of the vessel lumina. Clinically, HUS is characterized by the triad of microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia.7 Since 1994, occasional cases of HUS that followed chemotherapy with gemcitabine have been reported, and a crude overall incidence rate of 0.015% has been determined based on the manufacturer’s worldwide pharmacovigilance and epidemiology safety database.8 We present a case of HUS after prolonged treatment with gemcitabine for ovarian cancer. We also review the literature about this potentially fatal adverse event. CASE REPORT A 45-year-old woman was diagnosed with moderately differentiated adenocarcinoma of the ovary, FIGO IIIC stage, in November 1998. The patient underwent cytoreductive surgery with suboptimal resection. First-line chemotherapy with cisplatin/paclitaxel resulted in no tumor response. Second-line therapy with topotecan could not prevent radiologically documented tumor progression. After a short trial with tamoxifen, chemotherapy with carboplatin/paclitaxel was initiated, but the tumor progressed again. In July 1999, chemotherapy with weekly gemcitabine, 1,000 mg/m2, was begun.9,10 Gemcitabine was well tolerated, although several doses had to be omitted because of a low platelet count. Paracentesis was necessary for recurrent ascites. The tumor marker CA-125 decreased from 360 IE/mL (normal range, ⬍30 IE/mL) in July 1999 to 115 IE/mL in January 2000. Although CA-125 subsequently tended to increase, therapy was continued because the disease remained clinically stable. In May 2000, after a total dose of 70 g of gemcitabine, blood transfusions repeatedly were required because of progressive anemia. Subsequently, treatment with gemcitabine was discontinued. The decrease of hemoglobin was accompanied by deteriorating renal function with minimal measured creatinine clearance of 19.8 mL/min (0.33 mL/s), marked proteinuria (3.8 g/24 hours), microhematuria, thrombocytopenia of 69 ⫻ 103/L (69 ⫻ 109/L), increase in serum lactate dehydrogenase (LDH) (1,138 U/L; normal range, 150 to 420 U/L), peripheral edema, pleural effusions, hemorrhagic ascites, arterial hypertension (200/120 mm Hg), and thrombosis of the left internal jugular vein. Based on these features and a peripheral blood smear showing fragmented red blood cells, a diagnosis of microangiopathic hemolytic anemia was made. After discontinuation of gemcitabine therapy, laboratory parameters slowly improved over the next weeks and normalized in November 2000 without specific treatment. In February 2001, tumor progression caused massive ascites and abdominal pain. Because gemcitabine was considered the only effective therapy for this patient, oral informed consent was obtained for reexposure to the drug. Gemcitabine, 1,000 mg/m2, was administered with dexamethasone, 8 mg, in March 2001, and the latter was tapered over the next 2 days. Transient macrohematuria developed on the first day after reexposure to gemcitabine, however, and
persisted for 5 days. Because urinary bleeding initially was ascribed to tumor invasion of the lower urinary tract, a second dose of gemcitabine was administered after resolution of macrohematuria. Two days later, macrohematuria reappeared and was accompanied by slight increases of serum creatinine and LDH and a decrease of the platelet counts. Although no fragmented red blood cells were visible in the peripheral blood smear, chemotherapy with gemcitabine was discontinued because drug-induced renal toxicity was assumed. Subsequently, laboratory parameters returned to normal within the following weeks. No further chemotherapy was given, and the patient died in May 2001 as a result of progressive disease.
METHODS A MEDLINE search up to December 31, 2001, was conducted to identify previous reports of gemcitabineassociated HUS. The search was done by intersecting gemcitabine with acute uremia, hemolysis, hemolytic-uremic syndrome, HUS, microangiopathic hemolytic anemia, (acute) renal failure, thrombocytopenia, and thrombotic microangiopathy. Identified articles were read carefully for references to other articles eventually not found by MEDLINE. Only cases meeting classic clinical or histologic criteria for HUS were included in the review.
RESULTS
Including our own case and considering double and triple publications (one single case described by Brodowicz et al11 and Fung et al8; another case described by Casper et al,6 Flombaum et al,12 and Fung et al8; a third probably identical case reported by Lhotta et al13 and Fung et al8) a total of 26 different cases of HUS associated with gemcitabine were identified in the literature up to December 31, 2001.6,8,11-23 Because of the varying completeness of reporting, findings are not presented in tabular form. The first case of biopsy-proven HUS associated with gemcitabine monotherapy was reported in a phase II trial of patients with pancreatic adenocarcinoma in 1994.6 Another case of HUS was suspected in a patient with small cell lung cancer treated with gemcitabine.24 The possibility of HUS was considered only retrospectively based on clinical and laboratory findings. Shortly thereafter, two patients with metastatic adenocarcinoma of the lung were reported from another phase II trial. They developed acute renal failure 4 and 6 weeks after the last dose of gemcitabine. The diagnosis was confirmed in both cases by histology.25 In a review of the manufacturer’s database containing serious adverse events from clinical trials and spontaneous
GEMCITABINE-ASSOCIATED HUS
reports from postmarketing experience up to December 1997, 12 cases of HUS associated with single-agent gemcitabine were identified. All cases met either clinical (ie, acute uremia, microangiopathic hemolytic anemia, and thrombocytopenia) or histologic criteria (renal biopsy).7 This is the largest series of patients described to date.8 Single cases and small series of patients were reported by several investigators.11-23 Among the 26 cases of gemcitabine-associated HUS, 11 were on clinical trials, and 15 were identified by surveillance. There were 10 women and 12 men and 4 cases with unspecified sex. Median age was 52 years (range, 26 to 73 years; information available for 23 patients). Diagnosis included primary pancreatic (n ⫽ 12), small cell lung (n ⫽ 5), gastric (n ⫽ 1), ovarian (n ⫽ 2), transitional cell (n ⫽ 1), biliary (n ⫽ 1), and duodenal papillary (n ⫽ 1) cancers; hepatic adenocarcinoma with suspected pancreatic or cholangiocellular primary tumor (n ⫽ 1); malignant pleural mesothelioma (n ⫽ 1); and peripheral T cell lymphoma (n ⫽ 1). All tumors were at an advanced stage (23 patients). Prior chemotherapy had been administered to 10 patients: mitomycin-C in 1, 5-fluorouracil in 3, mitomycin/ 5-fluorouracil in 1, cisplatin/bleomycin/etoposide in 1, cyclophosphamide/leucovorin/5-fluorouracil/tamoxifen in 1, and high-dose cyclophosphamide/doxorubicin/vincristine/prednisolone/retinoic acid in 1. One patient had been treated with three different chemotherapy regimens (cyclophosphamide/cisplatin/epirubicin, taxol/carboplatin, and topotecan). As mentioned, our patient had been pretreated with cisplatin/ paclitaxel, topotecan, tamoxifen, and carboplatin/ paclitaxel. For one subject, no data were available about prior chemotherapeutic treatments. In one patient, carboplatin was administered concomitantly with gemcitabine. In another patient, HUS developed after 9 weekly administrations of gemcitabine, which followed a prior combined treatment with locoregional mitomycin C and systemic gemcitabine for seven cycles. One patient was treated with gemcitabine for four cycles for advanced small cell lung cancer. After developing side effects resembling capillary leak syndrome, he was withdrawn from the study, then received one cycle of chemotherapy with carboplatin and vindesine; subsequently, HUS
3
developed 5 weeks after initiation of the secondline therapy. Diagnosis of HUS was confirmed by renal biopsy or autopsy in 13 patients. All these patients had laboratory findings of hemolytic anemia, and only two cases lacked fragmented red blood cells on peripheral blood smears. No biopsy was done in 10 patients, but diagnosis was ascertained by features of microangiopathic hemolytic anemia with fragmented red blood cells. In one patient with acute uremia, anemia, transient thrombocytopenia, rising LDH, and low haptoglobin levels, a skin biopsy was done for evaluation of livedo reticularis, revealing focal intravascular fibrin, slight dermal fibrosis, and focal lymphohistiocytic inflammatory cell infiltrates at the dermal-subcutaneous junction suggesting generalized microvascular toxic effects. In two patients, the criteria for diagnosis were not indicated. New-onset thrombocytopenia was noted in 20 of 20 subjects for whom this information was available. New-onset hypertension or exacerbation of underlying hypertension was present in 15 of 21 subjects. Dyspnea, with or without pulmonary edema, was found in 12 of 22 assessed patients. Edema of the ankles or lower legs was described in four patients, ascites in two (with one of them suffering from advanced ovary cancer), pleural effusion in two, pericardial effusion in one, cardiomegaly in one, lung infiltrates in one, self-limiting diarrhea in one, and nonspecific central nervous system symptoms (eg, headache, blurred vision, or confusion) in six. Two subjects presented with livedo reticularis of the legs and had skin ulcers. In both of them, cryoglobulins were found positive or trace positive during the course of illness. The mean duration between initiation of gemcitabine therapy and onset of HUS was 7.4 ⫾ 3.5 months (range, 2.5 to 16 months), corresponding to approximately 21.9 ⫾ 10.9 applications (range, 7 to 48 applications). These are only approximate values, however, because information concerning the duration of treatment and scheduling of gemcitabine was missing in one patient and was limited in others. Similarly, information on the cumulative dose was missing in 1 patient; for 5 patients, only total-milligram doses were noted, whereas for 20, the dose was indicated in mg/m2. For estimation, we assumed the five patients to
4
be 1.73 m2. The resulting calculated median cumulative dose was 20,000 mg/m2 (range, 2,450 to 48,000 mg/m2, or a total of 70,000 mg). Although HUS developed during chemotherapy with gemcitabine in some patients, the onset of HUS was noted up to 2 months after the last infusion in others. Gemcitabine was discontinued without the need for further treatment in two patients (our case and another patient who also improved spontaneously). A variety of different treatments were tried in the remaining patients, including fresh frozen plasma without improvement of renal function in one patient, and steroids with at least stabilization of renal function in two patients. In another case, steroids were unsuccessful, and the patient underwent transient hemodialysis with subsequent improvement of renal function. Dialysis was applied to an additional eight patients, and one patient was treated with absorption chromatography. In only two of these patients, an improvement of renal function was noted. In one patient, death was attributed to acute renal failure, and in one patient death was suspected to be due to the consequences of thrombotic microangiopathy. Two patients were treated with plasmapheresis, with one patient recovering almost completely. A third patient was treated successfully with a short course of steroids after a single plasma exchange. A fourth patient temporarily improved after plasmapheresis and steroids but relapsed and remained refractory to further treatment soon thereafter. Dialysis and plasmapheresis were applied in two patients, with one showing an improvement in renal function, whereas the other died as a result of renal failure and further complications. One patient underwent plasmapheresis and splenectomy and received immunoglobulins resulting in improved renal function. Hemolysis resolved in one patient treated with hemodialysis, plasmapheresis, and steroids, but chronic renal failure persisted. Renal function finally improved in one patient treated with fresh frozen plasma, a single hemodialysis session, and plasmapheresis. Treatments and outcome were not reported in two patients. Reexposure to gemcitabine was reported in two additional patients besides our patient. In one patient, the drug was reintroduced several months later because of tumor progression. After the administration of 3,000 mg, the patient was
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noted to “do well without any recurrence of HUS.” In a second patient in whom reintroduction was attempted, an acute myocardial infarction occurred after the second dose, resulting in death. A postmortem examination was not done, but laboratory examinations were not suggestive for recurrent HUS at the time of the cardiac event. DISCUSSION
Mechanisms of chemotherapy-induced renal dysfunction include prerenal perfusion deficits, damage to vessels or other structures of the kidneys, and HUS.26 HUS is a devastating, potentially fatal multisystem process characterized clinically by thrombocytopenia, microangiopathic hemolytic anemia, impaired renal function, and neurologic dysfunction and histologically by thrombotic microangiopathy.7 Its pathophysiology is incompletely understood, but endothelial injury is the central feature and likely inciting factor. Abnormalities in thromboresistance, leukocyte adhesion, complement, von Willebrand factor, and vascular shear stress may sustain and amplify the microangiopathic process.7 It has long been recognized that HUS may occur in cancer patients not receiving chemotherapy,27 and this strongly suggests the presence of disseminated disease.28,29 A growing number of chemotherapeutic agents, principally mitomycin C but also cisplatin and bleomycin, have been linked to the development of HUS. Gemcitabine has no structural similarity to those drugs but is related to cytosine-arabinoside (cytarabine), a drug that so far has been associated with HUS only anecdotally in combination with other chemotherapeutic agents.30,31 The incidence of HUS after treatment with mitomycin C varies from less than 2% to 10 or 15% but is much less common with other chemotherapeutic agents.29,32 The incidence of gemcitabine-associated HUS has been estimated to be 0.008% to 0.078% based on the manufacturer’s database of adverse events.8 It is possible, however, that the reported incidence increases as clinicians become more familiar with this diagnostic possibility. The time interval between chemotherapyinduced damage and the occurrence of HUS is extremely variable. The interval from the last
GEMCITABINE-ASSOCIATED HUS
dose of gemcitabine to the development of HUS ranged from 1 day to several months.28,29 Mitomycin-induced HUS is related to the cumulative dose.29 Gemcitabine-associated HUS developed after an estimated median cumulative dose of 20,000 mg/m2 with a range from 2,450 mg/m2 to 48,000 mg/m2, or a total of 70,000 mg. With this broad range, the association with the cumulative dose seems less clear-cut for gemcitabine. Because most gemcitabine-treated patients presenting with HUS have far advanced disease and some have received other agents known to be associated with HUS, the exact role of the underlying disease and chemotherapeutic agents is not easily delineated. Although microangiopathy caused by disseminated cancer and chemotherapy-associated HUS may represent two distinct syndromes, and distinguishing clinical and histologic features have been identified for these two conditions,29 there may be more similarities than differences.28 Nevertheless, clinical improvement after gemcitabine withdrawal in some cases and the result from reexposure to the drug in our case strongly suggest gemcitabine to be causative for HUS. It remains speculative whether the acute myocardial infarction that occurred after reexposure to the drug6,8,12 was unrelated to gemcitabine treatment or was due to undetected microvascular changes. Clinically, an individual patient with gemcitabine-associated HUS may present with worsening of anemia, thrombocytopenia, increments of LDH or serum creatinine, elevated blood pressure, dyspnea, peripheral edema, neurologic signs, or hematuria. Accurate diagnosis of the disorder may be delayed because anemia and thrombocytopenia may be attributed to myelotoxicity of the anticancer agent. Although an elevated reticulocyte count may be an important clue to the hyperregenerative hemolytic anemia characterizing HUS,19 it may be low because of prior blood transfusions or myelosuppression.22 When the diagnosis is suspected, peripheral blood smears should be screened for the presence of fragmented red blood cells; these were missing in only a few of the biopsy-proven cases of gemcitabine-associated HUS. Likewise, increased levels of LDH are observed frequently in tumor patients, but a marked increase in LDH should be noted on development of HUS.13 Coagulation tests, including prothrombin time, activated par-
5
tial thromboplastin time, and fibrin degradation products, remain normal, in contrast to patients presenting with disseminated intravascular coagulation. Because proteinuria and microscopic hematuria are frequent, it is unlikely that they can serve as an early screening method for impending gemcitabine-associated HUS. By contrast, an unexplained increase in serum creatinine should alert the clinician to this possibility. Today, glucocorticoids and plasma infusion may be used in the initial management, but plasma exchange is the mainstay of treatment.33,34 Nevertheless, chemotherapy-associated HUS remains a highly fatal disease, with a case-fatality rate of 50% to 70%,29,32,35 with early deaths usually related to direct complications of the syndrome.29 In the present review, 11 of 23 patients with reported outcome died within a few weeks after the onset of HUS, and in 2 cases death was believed to be a direct consequence of HUS. In conclusion, there are few confirmed cases of gemcitabine-associated HUS that have been published so far despite the widespread use of the drug. Although it seems rare, this disorder is potentially fatal, and ancillary treatments or antidotes improving outcome have not been identified. A high index of suspicion for HUS is essential when cancer patients are treated with gemcitabine, especially with prolonged therapy. Any worsening of anemia, thrombocytopenia, increments of LDH or serum creatinine, clinical deterioration with elevated blood pressure, dyspnea, peripheral edema, neurologic signs, or hematuria should prompt a careful evaluation and the timely discontinuation of gemcitabine. REFERENCES 1. Chu E, Mota AC, Fogarasi MC: Pharmacology of cancer chemotherapy: Antimetabolites, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 6). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 388-415 2. Aapro MS, Martin C, Hatty S: Gemcitabine—a safety review. Anticancer Drugs 9:191-201, 1998 3. Cortes-Funes H, Martin C, Abratt R, Lund B: Safety profile of gemcitabine, a novel anticancer agent, in nonsmall cell lung cancer. Anticancer Drugs 8:582-587, 1997 4. Green MR: Gemcitabine safety overview. Semin Oncol 23:32-35, 1996 (suppl 10) 5. Tonato M, Mosconi AM, Martin C: Safety profile of gemcitabine. Anticancer Drugs 6:627-632, 1995 (suppl 6) 6. Casper ES, Green MR, Kelsen DP, et al: Phase II trial
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of gemcitabine (2,2⬘-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 12:2934, 1994 7. Ruggenenti P, Noris M, Remuzzi G: Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 60:831-846, 2001 8. Fung MC, Storniolo AM, Nguyen B, Arning M, Brookfield W, Vigil J: A review of hemolytic uremic syndrome in patients treated with gemcitabine therapy. Cancer 85:20232032, 1999 9. Orlando M, Mandachain M: Gemcitabine in ovarian cancer. Semin Oncol 28:62-69, 2001 (suppl 10) 10. Ozols RF: The current role of gemcitabine in ovarian cancer. Semin Oncol 28:18-24, 2001 (suppl 7) 11. Brodowicz T, Breiteneder S, Wiltschke C, Zielinski CC: Gemcitabine-induced hemolytic uremic syndrome: A case report. J Natl Cancer Inst 89:1895-1896, 1997 12. Flombaum CD, Mouradian JA, Casper ES, Erlandson RA, Benedetti F: Thrombotic microangiopathy as a complication of long-term therapy with gemcitabine. Am J Kidney Dis 33:555-562, 1999 13. Lhotta K, Ku¨hr T, Rumpelt HJ, Wo¨ll E, Thaler J, Ko¨nig P: Thrombotic microangiopathy with renal failure in two patients undergoing gemcitabine chemotherapy. Am J Nephrol 19:590-593, 1999 14. Stadler WM, Kuzel T, Roth B, Raghavan D, Dorr FA: Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 15:3394-3398, 1997 15. Nackaerts K, Daenen M, Vansteenkiste J, Vandevelde A, Van Bleyenbergh P, Demedts M: Hemolytic-uremic syndrome caused by gemcitabine. Ann Oncol 9:1355, 1998 16. Berk SH, Schilsky RL: The association of gemcitabine and hemolytic uremic syndrome: A case report. J Invest Med 46:274A, 1998 (suppl S) 17. Choi M, Woywodt A, Go¨bel U, Schneider W, Kettritz R: Haemolytic uraemic syndrome after gemcitabine treatment for pancreatic carcinoma. Nephrol Dial Transplant 14:2523-2524, 1999 18. van Meerbeeck JP, Baas P, Debruyne C, et al: A phase II study of gemcitabine in patients with malignant pleural mesothelioma. Cancer 85:2577-2582, 1999 19. Serke S, Riess H, Oettle H, Huhn D: Elevated reticulocyte count—a clue to the diagnosis of haemolytic-uraemic syndrome (HUS) associated with gemcitabine therapy for metastatic duodenal papillary carcinoma: A case report. Br J Cancer 79:1519-1521, 1999 20. Klapdor R, Seutter E, Lang-Po¨lckow EM, Reichle H, Hinrichs A: Locoregional/systemic chemotherapy of locally advanced/metastasized pancreatic cancer with a combination of mitomycin-C and gemcitabine and simultaneous follow-up by imaging methods and tumor markers. Anticancer Res 19:2459-2469, 1999
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21. Gross M, Hiesse C, Kriaa F, Goldwasser F: Severe hemolytic uremic syndrome in an advanced ovarian cancer patient treated with carboplatin and gemcitabine. Anticancer Drugs 10:533-536, 1999 22. Eckel F, Lersch C, Erdmann J, Schmidt B, SchulteFrohlinde E: 42-ja¨hriger Patient mit ha¨molytisch-ura¨mischem Syndrom unter Gemcitabin-Therapie eines Adenokarzinoms der Leber. Ha¨molytisch-ura¨misches Syndrom und Gemcitabin. Z Gastroenterol 38:593-596, 2000 23. Dumontet C, Morschhauser F, Solal-Celigny P, et al: Gemcitabine as a single agent in the treatment of relapsed or refractory low-grade non-Hodgkin’s lymphoma. Br J Haematol 113:772-778, 2001 24. Abratt RP, Bezwoda WR, Falkson G, Goedhals L, Hacking D, Rugg TA: Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: A phase II study. J Clin Oncol 12:1535-1540, 1994 25. Anderson H, Lund B, Bach F, Thatcher N, Walling J, Hansen HH: Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: A phase II study. J Clin Oncol 12:1821-1826, 1994 26. Kintzel PE: Anticancer drug-induced kidney disorders. Drug Saf 24:19-38, 2001 27. Brain MC, Dacie JV, Hourhaine DO: Microangiopathic haemolytic anaemia: The possible role of vascular lesions in pathogenesis. Br J Haematol 8:358-374, 1962 28. Gordon LI, Kwaan HC: Cancer- and drug-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Semin Hematol 34:140-147, 1997 29. Murgo AJ: Thrombotic microangiopathy in the cancer patient including those induced by chemotherapeutic agents. Semin Hematol 24:161-177, 1987 30. Okumura H, Nakamura S, Ohtake S, et al.: Hemolytic uremic syndrome developing during remission of acute myelomonocytic leukemia. Am J Hematol 44:66-67, 1993 31. Byrnes JJ, Baquerizo H, Gonzalez M, Hensely GT: Thrombotic thrombocytopenic purpura subsequent to acute myelogenous leukemia chemotherapy. Am J Hematol 21:299304, 1986 32. Lesesne JB, Rothschild N, Erickson B, et al: Cancerassociated hemolytic-uremic syndrome: Analysis of 85 cases from a national registry. J Clin Oncol 7:781-789, 1989 33. Kwaan HC, Soff GA: Management of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Semin Hematol 34:159-166, 1997 34. Neild GH: Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura: Pathophysiology and treatment. Kidney Int Suppl 64:S45-S49, 1998 35. Sheldon R, Slaughter D: A syndrome of microangiopathic hemolytic anemia, renal impairment, and pulmonary edema in chemotherapy-treated patients with adenocarcinoma. Cancer 58:1428-1436, 1986