Fatal outcome of a hypersensitivity reaction to paclitaxel: a case report

INTRODUCTION


A hypersensitivity reaction (HSR), defined as any immunological response to a drug resulting in an adverse reaction, is a frequent side-effect during chemotherapy infusion [Zanotti, 2001]. Chemotherapy-associated HSR may be caused by a Gell and Coombs type I, II, III and/or IV reaction. Symptoms vary from mild pruritus to systemic anaphylaxis with catastrophic outcome [Weiss, 1990]. The occurrence of HSRs can be influenced by administration of an appropriate premedication. Administration of histamine H1- and H2-receptor antagonists and corticosteroids, has been shown to significantly reduce the risk of developing a HSR in patients receiving taxanes [Verweij, 1994; Trudeau, 1996]. However, despite proper premedication, HSRs remain a threat to patients receiving chemotherapy [Weiss, 1990]. As an example of the latter, we describe in this case report the fatal outcome of a HSR in a patient after infusion of paclitaxel, despite administration of a widely accepted premedication regimen.



CASE REPORT


A 52 years old male with good performance status was referred for treatment of biopsy proven non-small cell lung cancer. The primary lesion was located in the left upper lobe with multiple pleural metastases and thoracoscopic invasion of the mediastinum (stage IV). Metastases in the liver and adrenal glands were excluded and his medical history and physical examination did not show evidence indicating central nervous system involvement. Routine baseline analyses, including ECG and blood testing, showed no abnormalities.

The patient was offered palliative chemotherapy and gave his oral informed consent. The planned treatment consisted of paclitaxel (200 mg/m2) as a 3-hourly infusion followed by carboplatin (area under curve 6) infusion, both as 3-weekly cycles. Premedication consisted of intravenously (iv) administered clemastine (2 mg), ranitidine (50 mg) and dexamethasone (10 mg) and was given 30 minutes prior to paclitaxel infusion. Shortly after the start of the paclitaxel infusion, the patient complained of acute progressive pain in his lower back, dyspnea, chest pain and developed general distress, followed by cardiac arrest. Cardiopulmonary resuscitation, which included intubation and respiratory support, was started without delay and remained unsuccessful. An autopsy was performed confirming the presence of a large cell undifferentiated carcinoma in the left upper lobe. The tumor extended beyond the parietal pleura into the adjacent soft tissue; there was no direct invasion of the brachial plexus nerves. Additional findings included mild left ventricular hypertrophy and biventricular dilatation with moderate atherosclerosis of the coronary arteries. The spleen and liver were congested.



DISCUSSION


In this report we describe the fatal outcome of an acute onset HSR after paclitaxel infusion, despite administration of a widely accepted regimen of premedication. Postmortem findings after anaphylactic reactions and especially medication-induced anaphylaxis are generally non-specific and include pulmonary congestion and edema. Findings indicating an immunological (allergic) cause of death include cutaneous erythema, upper airway edema and petecchial hemorrhages are rarely seen [Pumphrey, 2000].
Paclitaxel is widely used as anti-tumor medication in ovarian, breast, non-small cell lung and other cancers. Due to the insolubility of paclitaxel, the compound requires Cremophor EL, a derivative of castor oil, as solubilizer.
Although the incidence of HSR after paclitaxel infusion is estimated to be approximately 10% [Markman, 2000], fatal outcome is rare. It is known that HSRs predominantly occur during the first 10 minutes of infusion and are usually restricted to the first 2 cycles of chemotherapy [Weiss, 1990].



The etiology of paclitaxel associated HSR is multifactorial. It is thought to be primarily mediated by an IgE-mediated mast-cell degranulation (type I reaction) induced by paclitaxel [Weiss, 1990 #1] or Cremophor EL [Weiss, 1987; Dye, 1980]. This non IgE-mediated idiosyncratic mast-cell degranulation by paclitaxel or by Cremophor EL is another important pathway for inducing HSR. However, some authors question the importance of Cremophor EL as a causative factor for HSR in paclitaxel treated patients [Nolte, 1988]. The rapid and overwhelming onset of the HSR as observed in our patient is not compatible with the natural course of an IgE hypersensitivity (type I) reaction and points towards an other mechanism.



The incidence of paclitaxel induced HSR is significantly reduced in patients receiving premedication, which includes corticosteroids [Kintzel, 2001]. Dexamethasone is a long-acting glucocorticoid with a biologic half-live of approximately 48 hours and noticeable onset of biologic activity is observed after several hours. Dexamethasone strongly inhibits inflammation, especially cellular-mediated immunity and the production or action of the local mediators of inflammation, such as the prostaglandins and lymphokines. Furthermore, dexamethasone reduces vascular permeability and maintains normal vascular responsiveness to circulating vasoconstrictor factors. Standard premedication with dexamethasone at a dose of 20 mg and given orally 12 and 6 hours prior to paclitaxel infusion was shown to prevent HSR in most cases [Weiss, 1990; Rowinsky, 1995]. However, this treatment regimen requires a high compliance of patients. To avoid rescheduling chemotherapy schemes due to non-compliance, attention was focused on anecdotal cases in which dexamethasone was administered shortly before paclitaxel infusion [Bookman, 1997]. In several retrospective series, 5-20 mg of dexamethasone administered iv 30 minutes before the infusion of paclitaxel was shown to be equally successful as the oral pre-medication in historical cases [Kintzel, 2001]. However, this short-course premedication schedule, is unlikely to result an adequate level of immunosuppression before the start of infusion of paclitaxel. It is possible that the observed effect of short-course iv prophylaxis by dexamethasone is biased by retrospective analysis and comparison of the study cohort with historical controls. A prospective randomized study in which the oral pre-treatment regimen is compared with the short-course iv administration of dexamethasone is to be preferred. If the patient is pre-treated with the short-course iv administration of dexamethasone, his/her physician should be aware of the limited level of evidence supporting this procedure.



In conclusion, the fatal outcome of the paclitaxel-associated HSR in the patient, despite adequate premedication and resuscitation, illustrates the need for continues awareness and questions the value of routine iv premedication.



Acknowledgement

The authors thank A.J. Gelderblom for critically reading the manuscript.



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CORRESPONDING AUTHOR

Jan P. van Meerbeeck

vanmeerbeeck@svlo.azr.nl