Case Report Headache, Circumoral Paresthesia, and Facial Flushing

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

1Division of Pharmacy and 2Department of Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Summary: front-line chemotherapy, the patient received high-dose chemotherapy with granulocyte colony-stimulating factor We describe seven patients who developed symptoms (G-CSF) stimulated autologous peripheral blood stem cell including severe headache, circumoral paresthesia, and (PBSC) transplantation. The conditioning regimen con- facial flushing during high-dose carmustine (BCNU) sisted of: cyclophosphamide 2 g/m2 in 5% dextrose injec- infusion as part of the preparative regimen for autolog- tion USP (D5W) 500 cc i.v. over 2 h on days −6to−4, ous peripheral blood stem cell (PBSC) transplantation thiotepa 240 mg/m2 in 0.9% sodium chloride USP 250 cc for metastatic breast cancer. Five patients responded to i.v. over 4 h on days −6to−4, and BCNU 150 mg/m2 in pain medications, including partial and complete opiate D5W 500 cc i.v. over 2 h on days −6to−4. Day 0 rep- receptor agonists. Premedication of subsequent doses of resented the day of transplantation. During the infusion of BCNU with corticosteroids, pain medications, or benzo- BCNU, the patient developed a unilateral frontal crushing diazepines lessened, but did not prevent the same symp- headache, circumoral paresthesia, photophobia, and facial toms from recurring. The incidence and mechanism of flushing. The patient was treated with propoxyphene 130 this toxicity are unknown, but this adverse syndrome mg p.o. and hydromorphone 1 mg i.v. which relieved the should be considered when administering high-dose pain. Laboratory values were within normal limits. Sub- BCNU infusions. sequent doses of BCNU were pre-medicated with hydro- Keywords: carmustine; autologous PBSC transplan- morphone 0.5 mg i.v. and hydrocortisone 50 mg i.v. The tation; headache; circumoral paresthesia; flushing patient experienced similar, but less severe, symptoms which responded to propoxyphene. CT of the head and magnetic resonance imaging of the brain were both nega- tive. The patient completed the chemotherapeutic regimen Carmustine (BCNU) is commonly used as part of the con- and received the autologous PBSC transplant without com- ditioning regimen for autologous bone marrow transplan- plications. She became neutropenic on day 2, recovered 1,2 tation (ABMT) for metastatic breast cancer. Side-effects hematopoiesis on day 9, and was discharged on day 17. 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 Discussion infusion. A number of adverse effects have been caused by high- dose BCNU therapy, including severe nausea and vomiting, Case report encephalopathy, and cardiac, hepatic, and pulmonary tox- icities.1,3 In about 90% of patients, hepatotoxicity has mani- A 50-year-old patient with stage IV infiltrating ductal carci- fested as a transient elevation in transaminase concen- noma received seven cycles of adjuvant chemotherapy trations to two times the normal values within a week of (5-fluorouracil, doxorubicin, cyclophosphamide), which initiating treatment.4 These levels have usually normalized resulted in a partial response. A computed tomography within a week. Alkaline phosphatase abnormalities have (CT) scan showed a decrease in size of hepatic lesions; occurred later and have resolved more slowly.3 However, tumor markers improved, but did not normalize. The patient 5% to 20% of patients have developed veno-occlusive dis- was subsequently treated with tamoxifen, during which the ease of the liver,2,5 a potentially fatal syndrome.6 Late disease remained stable. Because of the poor prognosis of neurologic deterioration has been observed leading to patients not achieving complete remission with standard 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 Correspondence: C Ippoliti, The UT MD Anderson Cancer Center, Division of Pharmacy, 1515 Holcombe Boulevard Box 90, Houston, TX chest pain during infusion, concurrent with reversible ST 77030, USA segment depression on electrocardiogram, but cardiac Received 15 July 1996; accepted 19 December 1996 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 Signs/symptoms Onset Treatment Reaction Time to Future Second reconstitution infusion to reaction premedication reaction time treatment

1 D5W 100 ml 40 min Pain in back of 20 min Acetaminophen 650 N — Hydrocortisone 50 Milder reaction throat, tongue, mg p.o. mg i.v., gums, teeth, lips, propoxyphene 130 headache mg p.o. 2 D5W 100 ml 40 min Jaw pain 60 min Propoxyphene 130 Y 60 min Hydromorphone 1 Mild burning of radiating to roof mg p.o., mg i.v., lorazepam 1 gums of mouth, hydromorphone 1 mg mg i.v. dysphagia, i.v. headache 3 D5W 150 ml 40 min Headache, immediate Hydromorphone 3 Y 120 min Hydrocortisone 50 Milder reaction burning mg i.v. mg i.v., lips/throat, pain propoxyphene 130 in teeth mg p.o. 4 D5W 150 ml 40 min Burning of 20 min Morphine 5 mg i.v. Y 30 min Hydrocortisone 100 Milder reaction mouth/throat, mg i.v., but still severe flushing hydromorphone 1 mg i.v. 5 D5W 500 ml 120 min Headache, pain in 20 min Propoxyphene 130 Y 120 min Hydrocortisone 50 Milder reaction roof of mouth, mg p.o., mg i.v., flushing hydromorphone 1 mg hydromorphone 0.5 i.v. mg i.v. 6 D5W 500 ml 120 min Facial/jaw pain, 45 min Hydromorphone 1 Y 60 min Diphenhydramine 25 Milder reaction flushing mg i.v. mg i.v., but still severe hydrocortisone 50 mg i.v. 7 D5W 500 ml 120 min Burning sensation 90 min None — — Hydrocortisone 100 No reaction of lips/gums mg i.v., propoxyphene 65 mg p.o.

D5W = 5% dextrose injection USP.

tion.1 Pulmonary complications are the most serious tox- tation. BCNU was initially reconstituted in D5W 100 ml icity, as their development is not predictable and often fatal. or 150 ml and infused over 40 min. However, the manufac- Approximately 1 to 6 months following BCNU therapy, turer reported intense skin flushing and conjunctival suf- 31% of patients have developed a pulmonary syndrome fusion within 2 h of administration associated with rapid characterized by sudden onset of progressive exertional intravenous infusion. This was related to the absolute alco- dyspnea and a slight dry cough, often with fever.1 Ensuing hol diluent in each vial of BCNU. Consequently, sub- infections by opportunistic pathogens, such as cytomegalo- sequent doses of BCNU were diluted in D5W 500 ml and virus,4 and severe interstitial pneumonitis have been preva- infused over 2 h. Despite this change, an additional three lent.8 Pulmonary function tests (PFTs) have shown restric- patients developed the same adverse effects. Patients were tion, a reduced diffusing capacity for carbon monoxide, and treated with pain medications, including acetaminophen, hypoxemia.1 Open-lung biopsy has revealed hypertrophy morphine, and hydromorphone. All but one patient and hyperplasia of type II pneumocytes, active mono- responded to therapy by the end of BCNU infusion. The nuclear cell infiltration and inflammation, and interstitial patients continued to receive subsequent doses of BCNU. edema.3 In contrast, chest radiographs have inconsistently Premedication with a combination of diphenhydramine, revealed interstitial changes.1 Despite resolution of clinical hydrocortisone, hydromorphone, lorazepam, or propoxy- symptoms, PFTs have often remained abnormal for phene diminished the severity of subsequent reactions. extended periods, making PFTs important monitoring The mechanism of toxicity is unknown but may be tools.1 related to cytokine release. Increased concentrations of We report seven metastatic breast cancer patients who interleukin-6, tumor necrosis factor-␣, macrophage colony- developed adverse effects with high-dose BCNU never pre- stimulating factor, and erythropoietin have been reported in viously described in the literature (Table 1). Four patients patients receiving CSF-primed peripheral blood progenitor developed severe headaches, three experienced facial cells after chemotherapy resulting in differences in platelet flushing, and all seven patients had circumoral paresthesia reconstitution and organ toxicity.9 All of our reported within 90 min of the start of their first dose of BCNU. patients received G-CSF stimulation for autologous periph- These patients received BCNU 150 mg/m2 as part of their eral stem cell collection, but endogenous cytokine concen- conditioning regimen prior to autologous PBSC transplan- trations were not measured. These side-effects are also not Carmustine toxicity in autologous transplantation MH Woo et al 847 related to the administration of the other chemotherapeutic 2 Peters WP, Shpall EJ, Jones RB et al. High-dose combination agents, cyclophosphamide or thiotepa, as determined by alkylating agents with bone marrow support as initial treat- temporal proximity, although bolus doses of cyclophos- ment for metastatic breast cancer. J Clin Oncol 1988; 6: phamide have resulted in a milder, reversible oropharyngeal 1368–1376. sensation, urticaria, tongue-burning sensation, facial flush- 3 Takvorian T, Parker LM, Hochberg FH, Canellos GP. Auto- 10 logous bone-marrow transplantation: host effects of high-dose ing, diaphoresis, headache, and myxedema. BCNU. J Clin Oncol 1983; 1: 610–620. Although it is not known which patients are at risk for 4 Peters WP, Eder JP, Henner WD et al. High-dose combination developing this toxicity, we suggest reconstitution of high- alkylating agents with bone marrow support: a phase I trial. dose BCNU in at least 500 ml of D5W to be run over at J Clin Oncol 1986; 4: 646–654. least 2 h. If severe headache, pain, and burning of the 5 Ayash LJ, Hunt M, Antman K. Hepatic occlusive disease in mouth, throat, tongue, or lips develop, treatment with pain autologous bone marrow transplantation of solid tumor and medications, such as propoxyphene, hydromorphone, or lymphomas. J Clin Oncol 1990; 8: 1699–1706. morphine, is effective. Premedication of ensuing doses with 6 McIntyre RE, Magidson JG, Austin GE, Gale RP. Fatal veno- a combination of corticosteroid, antihistamine, benzodia- occlusive disease of the liver following high-dose 1,3-bis(2- zepine, or pain medication appears to prevent or minimize chloroethyl)-1-nitrosourea (BCNU) and autologous bone mar- the severity of subsequent reactions. The incidence of row transplantation. Am J Clin Pathol 1981; 75: 614–617. 7 Burger PC, Kamenar E, Schold SC et al. Encephalopathy fol- BCNU-induced headache, perioral paresthesia, and flushing lowing high-dose BCNU therapy. Cancer 1981; 48: 1318– is unknown, but this adverse syndrome should be con- 1327. sidered when administering high-dose BCNU, a drug fre- 8 Philips GL, Wolff SN, Fay JW et al. Intensive 1,3-bis(2- quently used as part of conditioning regimens for ABMT chloroethyl)-1-nitrosourea (BCNU) monochemotherapy and and autologous PBSC transplantation. autologous marrow transplantation for malignant glioma. J Clin Oncol 1986; 4: 639–645. 9 Rabinowitz J, Petros WP, Stuart AR, Peters WP. Characteriz- References ation of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support. Blood 1 Peters WP, Ross M, Vredenburgh JJ et al. High-dose chemo- 1993; 81: 2452–2459. therapy and autologous bone marrow support as consolidation 10 Arena PJ. Oropharyngeal sensation associated with rapid after standard-dose adjuvant therapy for high-risk primary bre- intravenous administration of cyclophosphamide (NSC- ast cancer. J Clin Oncol 1993; 11: 1132–1143. 26271). 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