Gemcitabine and haemolytic-uraemic syndrome

Gemcitabine is a pyrimidine antimetabolite with a broad spectrum of activity, and is used in pancreatic carcinoma. The main dose-limiting side-effects are myelosuppression, vomiting, flu-like symptoms, and in rare cases, haemolytic-uraemic syndrome (HUS). We report a patient who developed HUS related to the administration of gemcitabine therapy.

A 54-year-old man underwent a duodenopancreatectomy after a carcinoma of the pancreas was detected. The tumour and the two involved lymph nodes were removed.

Fifteen months later, local relapse and multiple pulmonary metastases were detected; subsequently, chemotherapy with intravenous gemcitabine (1000 mg/m2 on days 1, 8 and 15) and tegafur orally (400 mg every 12 h for 21 days), both every 4 weeks, was initiated.

After the fourth course, the patient was dyspnoeic and hypertensive, and suffered from daily chest pain, which suggested the existence of angina pectoris. Laboratory analyses revealed a haemolytic anaemia (haemoglobin 6.9 g/dl; indirect bilirubin and LDH elevated; decreased haptoglobin; increased reticulocyte count; negative direct Coombs; fragmentocytes on peripheral blood smear), deteriorating renal function and thrombocytopenia.

Because of these clinical and analytical findings, we diagnosed haemolytic-uraemic syndrome; therapy with corticosteroids was begun and we considered plasmapheresis. This was not possible because the patient underwent a new episode of angina pectoris and, later, a myocardial infarct.

In the light of the serious situation and poor prognosis, it was decided not to adopt aggressive measures and to apply a symptomatic treatment; the patient died in the following hours.

HUS is a thrombotic microangiopathy characterised by microangiopathic haemolytic anaemia, thrombocytopenia and renal failure.

HUS is caused by several factors such as infectious diseases, malignancy, autoimmunity, pregnancy and drugs. Numerous drugs are implicated, including chemotherapeutic drugs such as mitomycin C, and more rarely, gemcitabine (incidence of 0.008–0.078%) [1Go].

Casper et al. [2Go] were the first to report the association of gemcitabine therapy and HUS. The mechanism is unknown, although endothelial activation may be involved. Erythrocyte fragmentation and renal failure are caused by the occlusion of arteries and arterioles by platelets and fibrinoid thrombi. The renal biopsy shows a thrombotic microangiopathy, with prominent thickening of the glomerular capillary wall [3Go].

The patient's clinical history and the laboratory findings were compatible with HUS, which occurred in conjunction with gemcitabine administration. Haemolytic-uraemic syndrome appears to be more frequent among males aged 50–69, but this may be more representative of the natural disease prevalence (lung or pancreatic carcinoma) rather than of any gender or age sensitivity to this event [4Go].

Although a dose–response relation is well documented for mitomycin C-induced HUS, a dose or duration effect has been difficult to establish with gemcitabine. Our patient had received a cumulative dose of 10 000 mg/m2. Walter et al. reported a cumulative dose of 20 000 mg/m2 (range, 2450–48 000 mg/m2) and a mean duration between initiation of gemcitabine therapy and onset of HUS of 7.4±3.5 months or 21.9±10.9 applications of the drug [1Go].

The main treatment for patients with HUS is plasmapheresis, as well as corticosteroids, haemodialysis and immunosuppressive therapies. Despite these treatments, HUS still has a poor prognosis, with a mortality rate around 50% [5Go].

HUS is a relatively rare side-effect of gemcitabine therapy. Early attention to renal function and haemogram may help to prevent it.

I. Ruiz*, J. Del Valle and A. Gómez

Department of Medical Oncology, Hospital Clínico Universitario de Salamanca, Paseo San Vicente 58-182, 37007, Salamanca, Spain

* Email: mruizmartin{at}hotmail.com

References

1. Walter RB, Joerger M, Pestalozzi BC. Gemcitabine associated haemolytic uremic syndrome. Am J Kidney Dis 2002; 40(4): E16.[CrossRef][Medline]

2. Casper ES, Green MR, Kelsen DP et al. Phase II trial of gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 1994; 12: 29–34.[ISI][Medline]

3. Flombaum CD, Mouradiau JA, Casper ES et al. Thrombotic microangiopathy as a complication of long-term therapy with gemcitabine. Am J Kidney Dis 1999; 33: 555–563.[ISI][Medline]

4. Dilhuydy MS, Delclaux C, Pariente A et al. Syndrome hémolytique et urémique compliquant un traitemente au long cours par gemcitabine. Rev Med Interne 2002; 23: 189–192.[ISI][Medline]

5. Fung MC, Storniolo AM, Nguyen B et al. A review of hemolytic uremic syndrome in patients treated with gemcitabine therapy. Cancer 1999; 85: 2023–2031.[CrossRef][ISI][Medline]





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