174

simplified.9 All vaccinees with peak anti-HBs concentrations below 100 IU/1 should receive a booster dose within one year: subjects with a good immune response (100 IU/l or more) should be

on

revaccinated after five to seven years. By this strategy most individuals will maintain neutralising antibody concentrations; in the remainder the presence of the immunological memory will prevent disease. Antibody tests at exposure, as suggested by Dr Morris, cannot replace such a strategy since infections are not always transmitted by a noticeable event such as needle-stick injury.

Potential causes of the early severe mucositis and oropharyngeal oedema include chemoradiation therapy, especially etoposide,3 methotrexate, or an interaction between IFN and radiation. However, in 2 patients mucositis developed before all or any methotrexate had been given, and the third patient did not receive etoposide. Furthermore, none of 12 other patients conditioned with the same regimen had grade 4 mucositis at etoposide doses of under 65 mg!kg.3 Although the severity of the problem might be related to the use of an unrelated marrow donor, it was not seen with transplants from unrelated donors in other patients with stablephase chronic myelogenous leukaemia who had not received IFN but were conditioned with this regimen. Graeven et all reported no adverse effects of previous IFN treatment in 13 chronic myelogenous leukaemia patients conditioned for BMT without TBI. However, in these cases BMT was done at a median interval of 22 days (range 16-260) after stopping IFN. Although it is unclear how soon BMT may most safely be done after treatment for malignancy, we suggest that it may be advisable to stop IFN 2-3 weeks before starting conditioning therapy for BMT where TBI is used.

Maxvon Pettenkofer-Institute for Hygiene and Medical Microbiology, University of Munich, D-8000 Munich 2, West Germany

WOLFGANG JILG MARION SCHMIDT FRIEDRICH DEINHARDT

Jilg W, Schmidt M, Deinhardt F, Zachoval R. Hepatitis B vaccination: how long does protection last? Lancet 1984; ii: 458. 2. Ambrosch F, Frisch-Niggemeyer W, Kremsner P, et al. Persistence of vaccineinduced antibodies to hepatitis B surface antigen and the need for booster vaccination in adult subjects. Postgrad Med J 1987; 63 (suppl 2): 129-35. 3. Jilg W, Schmidt M, Deinhardt F. Persistence of specific antibodies after hepatitis B vaccination. J Hepatol 1988; 6: 201-07. 4. Gottlieb S, Martin M, McLaughlin FX, Panaro RJ, Levine L, Edsall G. Long-term immunity to diphtheria and tetanus: a mathematical model. Am J Epidemiol 1967; 1.

85: 207-19. 5.

Jilg W. Impfung gegen Hepatitis B. Impfstoffe, Wirkungsweise, Impfschutzdauer,

6.

Wiederimpfung. Dtsch Med Wochenschr 1989; 114: 596-98. Wainwright RB, McMahon BJ, Bulkow LR, et al. Duration of immunogenicity and efficacy of hepatitis B vaccine in a Yupik Eskimo population. JAMA 1989; 261:

2362-66. 7. Wismans PJ, van Hattum J, Mudde GC, Endeman HJ, Poel J, de Gast GC. Is booster injection with hepatitis B vaccine necessary in healthy responders? A study of the immune response. J Hepatol 1989; 8: 236-40. 8. Jilg W, Schmidt M, Deinhart F. Immune response to hepatitis B revaccination. JMed Viral 1988; 24: 377-84. 9. Workshop Report. Immunisation against hepatitis B. Lancet 1988; i: 875-76.

day

with

+ 1. On severe

day +9 intermittent respiratory distress started, oropharyngeal oedema that responded to

glucocorticoids.

Bone Marrow Transplantation Program and Department of Radiation Medicine, Lombardi Cancer Center,

Georgetown University, Washington DC, USA *Present address:

M. COTTLER-FOX* J. TORRISI T. R. SPITZER H. J. DEEG

Department of Transfusion Medicine, National Institutes of Health,

Bethesda, Maryland 20892, USA.

U, Beelen DW, Quabeck K, et al. Cytoreductive therapy with recombinant alpha-2B interferon pnor to allogeneic bone marrow transplantation for chronic myeloid leukaemia. Bone Marrow Transplant 1989; 4 (suppl 2): 74.

1. Graeven

Increased toxicity of total body irradiation in patients receiving interferon for leukaemia SIR,--Graeven and co-workers1 have suggested that ot-interferon (IFN) might be advantageous as first-line treatment for chronic myelogenous leukaemia patients before bone marrow transplantation (BMT).1 However, IFN is a radiation sensitiser reported to cause early severe mucositis and oesophagitis in combination with radiotherapy.2 We describe our experience in 3 stable-phase chronic myelogenous leukaemia patients who received IFN until just before total body irradiation (TBI) given in

preparation for BMT. Patient 1. 35-year-old man, marrow graft from an unrelated male donor, phenotypically identical for all but one (HLA-B) antigen. He received IFN 3 million units alternating with 5 million units subcutaneously for 2 years until the day before he began conditioning for BMT with TBI (120 cGy x 11), etoposide (60 mg/kgx 1), and cyclophosphamide (60 mg/kg x 2). He received methotrexate 10 mg/m2 on days + 1, + 3, and + 6 and cyclosporin for graft-versus-host disease (GVHD) prophylaxis. Grade 4 mucositis (defined as impending airway obstruction or lifethreatening haemorrhage) occurred on day + 9. On day + 10 he had an acute

respiratory arrest.

Patient 2. 22-year-old woman, marrow graft from an unrelated female donor, phenotypically identical for all but one (HLA-A) antigen. She received IFN 45 million units subcutaneously daily for 6 months until the day before she began the same conditioning regimen as patient 1. Grade 4 mucositis developed the day before marrow infusion. As GVHD prophylaxis she received cyclosporin and methotrexate 10 mg/m2 on day + 1 but because of persistently high methotrexate concentrations the remaining doses of methotrexate were not

2. Torrisi J, 3.

Berg C, Bonnem E, Dritschilo A. The combined

use

of interferon and

radiotherapy in cancer management. Sem Oncol 1986; 13: 78-83. Spitzer TR, Cottler-Fox M, Torrisi J, et al. Escalating doses of etoposide with cyclophosphamide and fractionated total body irradiation or busulfan as conditioning for bone marrow transplantation. Bone Marrow Transplant 1989; 4: 559-66.

Effect of dimethylsulphoxide on cholinergic neurotransmission in guineapig SiR,-Bond and colleagues1 reported a patient in whom severe encephalopathy developed after intravenous application of dimethylsulphoxide (DMSO). The pathogenesis of this side-effect is still a matter for speculation. We used DMSO as a solvent in our in-vitro experiments to try to characterise the cholinergic neurotransmission in isolated guineapig central airways by transmural electrical field stimulation (trains of square-wave pulses, train duration 10 s, impulse width 0-5 ms, frequency 30 Hz, amplitude 30 V). Such stimulation trains were repeated every 6 min. They caused strong cholinergic contractions followed by longlasting dilatations in isolated guineapig tracheal spirals. In control experiments with DMSO alone (n=9) we observed an enhancement of the cholinergic contractions induced by electrical field stimulation in this preparation (figure). This finding might result from increased permeability of the membranes of nerve endings at high DMSO concentrations.

given. Instead, glucocorticoids were begun on day

for GVHD prophylaxis and control of oropharyngeal oedema. Despite this threatment, she needed intubation. Patient 3. 39-year-old man, marrow graft from an HLA genotypically identical sister. He received IFN 5 million units subcutaneously daily for 15 months until 11 days before conditioning with TBI (120 cGy x 11) and cyclophosphamide (60 mg/kg x 2). He received methotrexate 10 mg/m2 on days + 1, + 3, and +6 and cyclosporin for GVHD prophylaxis. Severe oesophageal pain developed on the day of transplantation, and mucositis +7

Effect of DMSO trachea.

on

cholinergic contractions

in

guineapig

175

Interestingly the concentrations of DMSO used in our experiments and the serum DMSO concentrations described by Bond and co-workers (160 mg/dl 96 h after the last infusion of DMSO) are much the same. Thus it is intriguing to speculate about an enhancement of neurotransmission as a possible cause of DMSO-induced neurotoxicity. Department of Asthma, Research Institute for Lung Diseases and Tuberculosis, 1115 Berlin, East Germany

Ifosfamide by continuous infusion to prevent encephalopathy SIR,-Encephalopathy is a distressing side-effect of ifosfamide. Usually, but not always,l the central nervous system (CNS) toxicity is fully reversible. The metabolite chloroacetaldehyde has been implicated though we cannot confirm the putative threshold for encephalopathy of serum chloroacetaldehyde levels of above 80-100 lunol/1 suggested by Goren et al.2 In patients without CNS toxicity we found serum levels of up to 210 umol/1. Chloroacetaldehyde is difficult to measure in biological fluids because its half-life is only 3-5 min, and bedside stabilisation of samples (eg, with formaldehyde) is necessary.3 Other predisposing factors or metabolites may be the source of the encephalopathy. Besides renal function, age, and performance status" the method of administration may significantly influence the incidence of ifosfamide encephalopathy. The incidence of encephalopathy after oral ifosfamide, even with a low single dose, is striking and may be due to first-pass metabolism,S which has not been shown for cyclophosphamide. In our experience a daily dose of oral ifosfamide above 1-5 g/m2 will produce CNS toxicity in most patients, even in the presence of normal renal function and good performance status. Oral ifosfamide has therefore to be regarded as an experimental drug, requiring further dose-ranging studies. Since dose fractionation of ifosfamide increases the therapeutic index, the total dose is usually split over 3-5 days. Continuous administration over 3-5 days carries by far the lowest risk of encephalopathy and is clearly superior to the daily fractionated dosage or to the still experimental oral route (table). In 85 patients

with various malignancies treated with continuous ifosfamide/ mesna over 3-5 days (single agent or in various combinations) we have not seen a single episode of encephalopathy in 256 cycles. Furthermore nausea and vomiting was mild for most of these patients, oral metoclopramide usually controlling these symptoms. We recommend giving ifosfamide with mesna as a continuous INCIDENCE OF IFOSFAMIDE ENCEPHALOPATHY

——-—————————J__________!_____________

frequency

of

encephalopathy after oral, intravenous bolus, and mtravenous continuous administration significant (p < 0 0001, ) tMesna was co-administered continuously at a dose of 60-100% of Ifosfamide. At end of eydes patients received 1200 mg mesna intravenously and 800 mg orally after 4and8hh

several

are

Oncology,

Inselspital,

J. SCHREIBER J. SLAPKE

Curry SC, Dahl DW. Dimethylsulphoxide-induced encephalopathy. Lancet 1989; i: 1134-35.

in

over

ifosfamide levels

Institute for Medical University of Bern,

1. Bond GR,

*Difference

days. There is no evidence that high serum required for treating most malignancies (though for soft-tissue sarcoma further studies are needed 3). With the introduction of portable infusion pumps ambulatory chemotherapy has become an attractive option. infusion

CH-3010 Bern, Switzerland Institute for Clinical

T. CERNY M. CASTIGLIONE K. BRUNNER

Pharmacology,

University of Bern

A. KÜPFER

Oncology Service, Ospedale San Giovanni, Bellinzona

G. MARTINELLI

Department of Clinical Oncology, Newcastle General Hospital, Newcastle upon Tyne, UK

M. LIND

1. Watkin

SW, Husband DJ, Green JA, Warenius HM. Isofamide encephalopathy: a reappraisal. Eur J Cancer Clin Oncol 1989; 1303-10. 2. Goren MP, Wright RK, Pratt CB, et al. Dechlorethylation of ifosfamide and neurotoxicity. Lancet 1986; ii: 1219-20. 3. Cemy T, Kupfer A. Stabilization and quantitative determination of the neurotoxic metabolite chloroacetaldehyde in the plasma of ifosfamide treated patients. Proceedings of ECCO 5 (London, 1989): P0147. 4. Antman KH, Ryan L, Elias A, et al. Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol 1989; 7: 126-31. 5. Lind MJ, Margison JM, Cerny T, et al. Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma. Cancer Res 1989; 49: 753-57. 6. Cemy T, Margison JM, Thatcher N, et al. Bioavailability of ifosfamide in patients with bronchial carcinoma. Cancer Chew Pharm 1987; 18: 261-64. 7. Cemy T, Lind M, Thatcher N, et al. A simple outpatient treatment with oral ifosfamide and oral etoposode for elderly and poor prognosis patients with small cell lung cancer. Br J Cancer 1989; 60: 258-61. 8. Pratt CB, Douglas EC, Etcubanas EL, et al. Ifosfamide in pediatric malignant solid tumors. Cancer Chemother Pharmacol 1989; 24 (suppl): 24-27. 9. The Gastrointestinal Tumor Study Group. Ifosfamide is an inactive substance in the treatment of pancreatic carcinoma. Cancer 1989; 64: 2010-13. 10. Elias A, Ryan L, Sulkes A, et al. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol 1989; 7: 1208-16. 11. Elias A, Antman K, Eder J, et al. High dose ifosfamide with mesna uroprotection: phase I study. ASCO Proc 1989; 8: 264.

Ifosfamide

pharmacokinetics and neurotoxicity

SIR,-Ifosfamide given intravenously is sometimes associated with encephalopathy or milder central nervous system (CNS) toxicity. However, when given orally the drug causes a reversible encephalopathy in 50% of cases. This toxicity was noted before the concomitant

use of mesna,2 which suggests that ifosfamide (or its rather than mesna is responsible, but the precise cause metabolites) has not yet been identified. In a retrospective study we measured ifosfamide concentrations3 in timed plasma samples from four patients (previously described4) with carcinoma of the cervix who had CNS toxicity/encephalopathy when treated with intravenous ifosfamide 5 g/m2 and mesna given over 24 h followed by 3-2 g/m2 mesna over 12 h. The table shows clinical and pharmacokinetic data on these four patients plus data for other patients on the above ifosfamide/mesna regimen without evidence of CNS toxicity5 and for cervical carcinoma patients receiving 1 or 2 g/m2 ifosfamide intravenously every 24 h for 3 days.** Ifosfamide kinetic data from the four CNS toxicity patients were very similar to the published values for the other two groups. Data for oral ifosfamide 1-5 g/m2 also reveal no differences in ifosfamide clearance and distribution between patients with and without CNS toxicity. Goren et al7 described two patients with ifosfamide-associated CNS toxicity who had high plasma levels of the ifosfamide metabolite chloroacetaldehyde (dechlorethylation to this metabolite can represent up to 25% of ifosfamide metabolism). Ifosfamide neurotoxicity is probably due to an abnormally high level of a metabolite or an abnormal metabolic profile rather than abnormal pharmacokinetics of unchanged ifosfamide. Creaven et all reported that 23-49% of the plasma ifosfamide concentration was achieved in the cerebrospinal fluid (CSF) 3 h after a dose of 3 g/m in three patients, but the nitrobenzylpyridine