Headache, circumoral paresthesia, and facial flushing associated with high-dose carmustine infusion

Bone Marrow Transplantation, (1997) 19, 845–847  1997 Stockton Press All rights reserved 0268–3369/97 $12.00 Case report Headache, circumoral paresthesia, and facial flushing associated with high-dose carmustine infusion MH Woo1, C Ippoliti1, J Bruton1 , R Mehra2, R Champlin2 and D Przepiorka2 1 Division of Pharmacy and 2 Department of Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Summary: We describe seven patients who developed symptoms including severe headache, circumoral paresthesia, and facial flushing during high-dose carmustine (BCNU) infusion as part of the preparative regimen for autologous peripheral blood stem cell (PBSC) transplantation for metastatic breast cancer. Five patients responded to pain medications, including partial and complete opiate receptor agonists. Premedication of subsequent doses of BCNU with corticosteroids, pain medications, or benzodiazepines lessened, but did not prevent the same symptoms from recurring. The incidence and mechanism of this toxicity are unknown, but this adverse syndrome should be considered when administering high-dose BCNU infusions. Keywords: carmustine; autologous PBSC transplantation; headache; circumoral paresthesia; flushing Carmustine (BCNU) is commonly used as part of the conditioning regimen for autologous bone marrow transplantation (ABMT) for metastatic breast cancer.1,2 Side-effects of high-dose BCNU have been extensively reported, but we currently document the first cases of intense headache, circumoral paresthesia, and facial flushing during BCNU infusion. Case report A 50-year-old patient with stage IV infiltrating ductal carcinoma received seven cycles of adjuvant chemotherapy (5-fluorouracil, doxorubicin, cyclophosphamide), which resulted in a partial response. A computed tomography (CT) scan showed a decrease in size of hepatic lesions; tumor markers improved, but did not normalize. The patient was subsequently treated with tamoxifen, during which the disease remained stable. Because of the poor prognosis of patients not achieving complete remission with standard Correspondence: C Ippoliti, The UT MD Anderson Cancer Center, Division of Pharmacy, 1515 Holcombe Boulevard Box 90, Houston, TX 77030, USA Received 15 July 1996; accepted 19 December 1996 front-line chemotherapy, the patient received high-dose chemotherapy with granulocyte colony-stimulating factor (G-CSF) stimulated autologous peripheral blood stem cell (PBSC) transplantation. The conditioning regimen consisted of: cyclophosphamide 2 g/m2 in 5% dextrose injection USP (D5W) 500 cc i.v. over 2 h on days −6 to −4, thiotepa 240 mg/m2 in 0.9% sodium chloride USP 250 cc i.v. over 4 h on days −6 to −4, and BCNU 150 mg/m2 in D5W 500 cc i.v. over 2 h on days −6 to −4. Day 0 represented the day of transplantation. During the infusion of BCNU, the patient developed a unilateral frontal crushing headache, circumoral paresthesia, photophobia, and facial flushing. The patient was treated with propoxyphene 130 mg p.o. and hydromorphone 1 mg i.v. which relieved the pain. Laboratory values were within normal limits. Subsequent doses of BCNU were pre-medicated with hydromorphone 0.5 mg i.v. and hydrocortisone 50 mg i.v. The patient experienced similar, but less severe, symptoms which responded to propoxyphene. CT of the head and magnetic resonance imaging of the brain were both negative. The patient completed the chemotherapeutic regimen and received the autologous PBSC transplant without complications. She became neutropenic on day 2, recovered hematopoiesis on day 9, and was discharged on day 17. Discussion A number of adverse effects have been caused by highdose BCNU therapy, including severe nausea and vomiting, encephalopathy, and cardiac, hepatic, and pulmonary toxicities.1,3 In about 90% of patients, hepatotoxicity has manifested as a transient elevation in transaminase concentrations to two times the normal values within a week of initiating treatment.4 These levels have usually normalized within a week. Alkaline phosphatase abnormalities have occurred later and have resolved more slowly.3 However, 5% to 20% of patients have developed veno-occlusive disease of the liver,2,5 a potentially fatal syndrome.6 Late neurologic deterioration has been observed leading to dementia, and encephalopathy associated with cerebral white matter necrosis at autopsy has also been reported.7 Six percent of patients have experienced mild to severe chest pain during infusion, concurrent with reversible ST segment depression on electrocardiogram, but cardiac enzymes have not been diagnostic for myocardial infarc- Carmustine toxicity in autologous transplantation MH Woo et al 846 Table 1 Summary of patients experiencing BCNU toxicity Patient i.v. Fluid BCNU reconstitution infusion time Signs/symptoms Onset 1 Treatment D5W 100 ml 40 min Pain in back of throat, tongue, gums, teeth, lips, headache 20 min Acetaminophen 650 mg p.o. N 2 D5W 100 ml 40 min Jaw pain radiating to roof of mouth, dysphagia, headache 60 min Propoxyphene 130 mg p.o., hydromorphone 1 mg i.v. Y 3 D5W 150 ml 40 min Headache, burning lips/throat, pain in teeth 4 D5W 150 ml 40 min Burning of mouth/throat, flushing 5 D5W 500 ml 6 7 immediate Hydromorphone 3 mg i.v. Reaction Time to to reaction treatment Y 20 min Morphine 5 mg i.v. Y 120 min Headache, pain in roof of mouth, flushing 20 min Propoxyphene 130 mg p.o., hydromorphone 1 mg i.v. Y D5W 500 ml 120 min Facial/jaw pain, flushing 45 min Hydromorphone 1 mg i.v. Y D5W 500 ml 120 min Burning sensation of lips/gums 90 min None — — Future premedication Hydrocortisone 50 mg i.v., propoxyphene 130 mg p.o. Second reaction Milder reaction 60 min Hydromorphone 1 Mild burning of mg i.v., lorazepam 1 gums mg i.v. 120 min Hydrocortisone 50 mg i.v., propoxyphene 130 mg p.o. Milder reaction 30 min Hydrocortisone 100 Milder reaction mg i.v., but still severe hydromorphone 1 mg i.v. 120 min Hydrocortisone 50 mg i.v., hydromorphone 0.5 mg i.v. Milder reaction 60 min Diphenhydramine 25 Milder reaction mg i.v., but still severe hydrocortisone 50 mg i.v. — Hydrocortisone 100 No reaction mg i.v., propoxyphene 65 mg p.o. D5W = 5% dextrose injection USP. tion.1 Pulmonary complications are the most serious toxicity, as their development is not predictable and often fatal. Approximately 1 to 6 months following BCNU therapy, 31% of patients have developed a pulmonary syndrome characterized by sudden onset of progressive exertional dyspnea and a slight dry cough, often with fever.1 Ensuing infections by opportunistic pathogens, such as cytomegalovirus,4 and severe interstitial pneumonitis have been prevalent.8 Pulmonary function tests (PFTs) have shown restriction, a reduced diffusing capacity for carbon monoxide, and hypoxemia. 1 Open-lung biopsy has revealed hypertrophy and hyperplasia of type II pneumocytes, active mononuclear cell infiltration and inflammation, and interstitial edema.3 In contrast, chest radiographs have inconsistently revealed interstitial changes.1 Despite resolution of clinical symptoms, PFTs have often remained abnormal for extended periods, making PFTs important monitoring tools.1 We report seven metastatic breast cancer patients who developed adverse effects with high-dose BCNU never previously described in the literature (Table 1). Four patients developed severe headaches, three experienced facial flushing, and all seven patients had circumoral paresthesia within 90 min of the start of their first dose of BCNU. These patients received BCNU 150 mg/m2 as part of their conditioning regimen prior to autologous PBSC transplan- tation. BCNU was initially reconstituted in D5W 100 ml or 150 ml and infused over 40 min. However, the manufacturer reported intense skin flushing and conjunctival suffusion within 2 h of administration associated with rapid intravenous infusion. This was related to the absolute alcohol diluent in each vial of BCNU. Consequently, subsequent doses of BCNU were diluted in D5W 500 ml and infused over 2 h. Despite this change, an additional three patients developed the same adverse effects. Patients were treated with pain medications, including acetaminophen, morphine, and hydromorphone. All but one patient responded to therapy by the end of BCNU infusion. The patients continued to receive subsequent doses of BCNU. Premedication with a combination of diphenhydramine, hydrocortisone, hydromorphone, lorazepam, or propoxyphene diminished the severity of subsequent reactions. The mechanism of toxicity is unknown but may be related to cytokine release. Increased concentrations of interleukin-6, tumor necrosis factor-a, macrophage colonystimulating factor, and erythropoietin have been reported in patients receiving CSF-primed peripheral blood progenitor cells after chemotherapy resulting in differences in platelet reconstitution and organ toxicity.9 All of our reported patients received G-CSF stimulation for autologous peripheral stem cell collection, but endogenous cytokine concentrations were not measured. These side-effects are also not Carmustine toxicity in autologous transplantation MH Woo et al related to the administration of the other chemotherapeutic agents, cyclophosphamide or thiotepa, as determined by temporal proximity, although bolus doses of cyclophosphamide have resulted in a milder, reversible oropharyngeal sensation, urticaria, tongue-burning sensation, facial flushing, diaphoresis, headache, and myxedema.10 Although it is not known which patients are at risk for developing this toxicity, we suggest reconstitution of highdose BCNU in at least 500 ml of D5W to be run over at least 2 h. If severe headache, pain, and burning of the mouth, throat, tongue, or lips develop, treatment with pain medications, such as propoxyphene, hydromorphone, or morphine, is effective. Premedication of ensuing doses with a combination of corticosteroid, antihistamine, benzodiazepine, or pain medication appears to prevent or minimize the severity of subsequent reactions. The incidence of BCNU-induced headache, perioral paresthesia, and flushing is unknown, but this adverse syndrome should be considered when administering high-dose BCNU, a drug frequently used as part of conditioning regimens for ABMT and autologous PBSC transplantation. References 1 Peters WP, Ross M, Vredenburgh JJ et al. High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 1993; 11: 1132–1143. 2 Peters WP, Shpall EJ, Jones RB et al. High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer. J Clin Oncol 1988; 6: 1368–1376. 3 Takvorian T, Parker LM, Hochberg FH, Canellos GP. Autologous bone-marrow transplantation: host effects of high-dose BCNU. J Clin Oncol 1983; 1: 610–620. 4 Peters WP, Eder JP, Henner WD et al. High-dose combination alkylating agents with bone marrow support: a phase I trial. J Clin Oncol 1986; 4: 646–654. 5 Ayash LJ, Hunt M, Antman K. Hepatic occlusive disease in autologous bone marrow transplantation of solid tumor and lymphomas. J Clin Oncol 1990; 8: 1699–1706. 6 McIntyre RE, Magidson JG, Austin GE, Gale RP. Fatal venoocclusive disease of the liver following high-dose 1,3-bis(2chloroethyl)-1-nitrosourea (BCNU) and autologous bone marrow transplantation. Am J Clin Pathol 1981; 75: 614–617. 7 Burger PC, Kamenar E, Schold SC et al. Encephalopathy following high-dose BCNU therapy. Cancer 1981; 48: 1318– 1327. 8 Philips GL, Wolff SN, Fay JW et al. Intensive 1,3-bis(2chloroethyl)-1-nitrosourea (BCNU) monochemotherapy and autologous marrow transplantation for malignant glioma. J Clin Oncol 1986; 4: 639–645. 9 Rabinowitz J, Petros WP, Stuart AR, Peters WP. Characterization of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support. Blood 1993; 81: 2452–2459. 10 Arena PJ. 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