- Email: [email protected]
LOW FREQUENCY OF SLOW DEBRISOQUINE HYDROXYLATION IN A NATIVE CHINESE POPULATION
852 178 ([SD 50] nmol/1).4 The 24 h integrated growth hormone was 2-2 nmoljl (4-8 ng/ml) (normal in 5-10-year-old children 2-7 [06] nmol/1’-). The child has now been virtually symptom-free for a year since
starting on nebulised budesonide. He has been off oral steroids for 6 months and now no longer takes theophylline. When we first saw him he was on the 50th percentile for height and weight but his face looked puffy and his parents said he had been gaining weight rapidly. Since taking budesonide he is growing along the 10th percentile, which his parents say is his normal body build. This case has demonstrated the possibility of controlling an infant with severe, steroid-dependent asthma by means of the twice daily inhalation of nebulised budesonide. It has been possible to wean him off both oral prednisone and slow-release theophylline. We have now started treating a further three children, aged 19, 31, and 83 months, with nebulised budesonide. All three had been receiving single-dose alternate-morning prednisone 15-30 mg and all were weaned off the oral steroid within 4 weeks and theophylline within 2 months. We thank and for their
mnr
Values for for 24 h.
plasma cortisol and
IIVYI
growth
I
hormone measured
hourly
suspension of beclomethasone dipropionate administered through a nebuliser during tidal breathing for infants with severe airways obstruction.l-3 The lack of a clear benefit from this nebulised preparation-in contrast to the generally excellent response to the use of metered dose inhalers in older children-may have been related to the low drug concentration used (50 ug/ml), though a higher dose would have required a larger volume and much longer treatment times. Budesonide resembles beclomethasone dipropionate clinically and a suspension-in high concentration (1 mg/ml) has been prepared. We report the use of budesonide in an infant with severe, steroid-dependent asthma. At age 9 months a previously healthy boy began to have mild attacks of wheezing about once a month. The attacks worsened and at the age of 16 months he was admitted to hospital and then transferred to intensive care, where he was treated with bronchodilator drugs, aminophylline, and steroids. His condition improved but he continued to require steroids and was admitted twice more over the next 3 months. Severe breathlessness and wheeze persisted despite prednisone up to 40 mg daily. At age 19 months he was transferred to our unit. His condition deteriorated despite intravenous aminophylline and hydrocortisone, inhaled salbutamol, and intravenous isoprenaline (later, salbutamol). Because of exhaustion and a PCOz of 55 mm Hg he was put on a ventilator. He was extubated after 48 h and he was then gradually weaned onto slow-release theophylline, alternate morning oral prednisone, and regular inhalations of nebulised salbutamol. Out of hospital he continued to require large doses of prednisone, often given daily because of wheeze and breathlessness. On admission at age 21 months we decided to try nebulised budesonide as an alternative to high doses prednisone. 1 mg budesonide (1 ml suspension) was given twice daily through a Hudson nebuliser and open face mask powered by a compressor. 55 % of the drug was removed over the 5 min needed to complete the inhalation. He remained on theophylline and also inhaled nebulised salbutamol as needed. His condition was subsequently much improved and the prednisone dose was down to 5 mg every other morning 1 month later. The supply of budesonide then ran out temporarily and his prednisone requirement rose immediately. 2 weeks later he was back on budesonide and he was weaned off all oral prednisone 2122 months after that. He remained in excellent health with only the occasional use of inhaled salbutamol, though he took slow-release
theophylline as a precaution. 3 months after the last dose of oral prednisone the boy was admitted for adrenal function studies (figure). The 24 h integrated cortisol was 148 nmol/1 (5-3 ug/dl) (normal value in young adults
Draco/Astra, Sweden, for supplies of budesonide suspension help and encouragement.
Departments of Paediatrics and Endocnnology and Metabolism, Hadassah University Hospital, Jerusalem 91240, Israel
S. GODFREY A. AVITAL A. ROSLER A. MANDELBERG K. UWYYED
1. Storr J, Lenney CA, Lenney W. Nebulised beclomethasone dipropionate in preschool asthma. Arch Dis Child 1986; 61: 270-73 2. Webb MSC, Milner AD, Hiller EJ, Henry RL. Nebulised beclomethasone dipropionate suspension. Arch Dis Child 1986; 61: 1108-10. 3. Maayan C, Itzhaki T, Bar-Yishay E, Gross S, Tal A, Godfrey S. The functional response of infants with persistent wheezing to nebulised beclomethasone dipropionate Pediatr Pulmonol 1986; 2: 9-14 4. Zadik Z, De Lacerda L, De Carmargo AH, Hamilton BP, Migeon CJ, Kowarski AA. A comparative study of urinary hydroxycorticosteroids, urinary free cortisol and the integrated concentration of plasma cortisol. J Clin Endocrinol Metab 1980; 51: 1099-101. 5. Zadik Z, Chalew SA, Raiti S, Kowarski A. Do short children secrete insufficient growth hormone? Pediatrics 1985; 76: 355-60.
LOW FREQUENCY OF SLOW DEBRISOQUINE HYDROXYLATION IN A NATIVE CHINESE POPULATION
SIR,-Several genetic polymorphisms of drug oxidation have been established and ethnic differences in drug metabolism are widely known. The debrisoquine/sparteine type is the most studied polymorphism.1 The oriental group excreted less 4-hydroxydebrisoquine but more debrisoquine than the Caucasian group, and the frequency of debrisoquine hydroxylation deficiency was about 30% in Chinese subjects, mostly first or second generation immigrants from Hong Kong.2,3 In contrast, Nakamura et al4 found no poor metaboliser of desbrisoquine in 100 Japanese volunteers. It seems that the frequency of the poor metaboliser phenotype of debrisoquine hydroxylation varies in Far Eastern
population groups. We have studied 269 unrelated, randomly selected, native, normal Chinese volunteers (144 males) from 23 provinces and cities. All volunteers had had no recent illness, were receiving no drug, had no abnormalities on physical examinations, and no biochemical evidence of hepatic or renal dysfunction. Urine was voided immediately before an oral dose of 10 mg debrisoquine sulfate and was collected for the next 6 h. The concentrations of debrisoquine and 4-hydroxydebrisoquine were determined by gas
chromatography.s The frequency distribution of the logarithmically transformed data was bimodal (figure). The values of log metabolic ratio (MR) ranged from -0-68 to 1 63 (MR ranged from 0-21 to 43). Individuals could be phenotyped as either extensive metabolisers or as poor metabolisers with an MR of 10 or 12. Our findings showed that the frequency of the poor metaboliser phenotype of debrisoquine hydroxylation was about 0-7%. Mean recoveries of debrisoquine and 4-hydroxydebrisoquine in urine were 18 and 12%, respectively. Neither sex nor smoking habits affected debrisoquine hydroxylation in our population.
853
Frequency distribution of log debrisoquine/4-hydroxydebrisoquine metabolic ratio in 269 normal Chinese volunteers.
Soloan et al6 reported that the half-life of debrisoquine was 3h in extensive metabolisers in a Caucasian group. In 11of our extensive metabolisers, elimination rate constants were 0-25 and 0-28 h, half-lives were 2-78 and 2-73 h, and the times to reach the average maximum excretion rate were 1’67 and 1 35 for debrisoquine and 4-hydroxydebrisoquine, respectively. We thank the Chinese Council of Natural Sciences for support.
Department of Pharmacology, Beijing Medical University, Baijing, China
YA-CHING LOU LIU YING
Department of Clinical Pharmacology,
L. BERTILSSON F. SJOQVIST
Karolinska Institute, Huddinge, Sweden
patients in remission receiving maintenance therapy and for patients with evidence of myelotoxicity. The average dosages actually given were mitomycin C 6-3mg/m2, mitozantrone 6-2 mg/m2, and methotrexate 28-7 mg/m2. The dosages for the first two courses were mitomycin C 6-6 6 mg/m, mitozantrone 6’4mg/m, and methotrexate 29-9mg/m2; and by the fifth course, for those patients in remission, the dosages had been reduced to mitomycin C 5-3 3 mg/m2, mitozantrone 5-5 mg/m2, and methotrexate 26-3 mg/m2 with no evidence of loss of remission. Analysis of response showed no relation to drug dosages, indicating that a ceiling of activity had been achieved within this range. There was no significant association between dosages of any drugs and myelotoxicity, indicating that other factors, such as dose reduction for maintenance, prevailed. Significant subjective toxicity included nausea in only 28% of patients, vomiting in 12 %, alopecia in 5%, and stomatitis in 11 %. Apart from the three weekly outpatient visits for injections, most patients were able to benefit from symptomatic relief of tumour symptoms, with virtually no treatment toxicity. We have found the 3M combination to be effective palliative therapy for treatment of disseminated breast cancer, 60% of patients achieving objective remission. The severe myelosuppression reported by others probably relates to excessive dosages used in patients with compromised liver, renal, or bone marrow function. These circumstances should be be undertaken. Royal Marsden Hospital, Sutton, Surrey SM2 5PT
anticipated and dose modification should TREVOR J. POWLES SUSAN ASHLEY
A, Goodman A, Dougherty S, Ashford R Myelotoxicity of methotrexate, mitozantrone, and mitomycin C for treatment of advanced breast cancer. Lancet 1987; 1.915. 2. Jodrell DI, Iveson TJ, Smith IE. Myelosuppression after methotrexate, mitozantrone, and mitomycin C. Lancet 1978; i: 1211. 3. Morton AR, Anderson H, Howell A Myelosuppression after methotrexate, mitozantrone, and mitomycin C. Lancet 1987; i: 1494. 4. Powles TJ, Ashley SE, Forgeson GV, et al. Treatment of advanced breast cancer with mitomycin C, mitozantrone and methotrexate (3M) compared to micristine, anthracyclin and cyclophosphamide In: Bonadonna G, ed. Clinical progress with mitozantrone. London. Royal Society of Medicine Services, 1987: 1-7. 1. Marks
1. Eichelbaum M.
Polymorphic oxidation of debrisoquine and sparteine. In: Kalow W, Coedde HW, Agarwal DP, eds. Ethnic differences in reactions to drugs and xenobiotics. New York: Alan R Liss, 1986: 157-67. (Prog Clin Biol Res; vol 24.) 2. Kalow W. Ethnic differences m drug metabolism. Clin Pharmacokinet 1982; 7: 373-400. 3. Kalow W. Pharmacoanthropology: Drug metabolism. Fed Proc 1984, 43: 2326-31 4. Nakamura K, et al. Interethnic differences in genetic polymorphism of debnsoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Chn Pharmacol Ther 1985; 38: 402-08. 5. Lennard MS, et al. Determination of debrisoquine and its 4-hydroxy-metabolite in biological fluids by gas chromatography with flame-isonization and nitro-selective detection. J Chromatogr 1977; 133: 161-66. 6. Soloan TP, et al. Genetically determined oxidation capacity and the disposition of debrisoquine. Br J Clin Pharmacol 1983; 15: 443-50.
MYELOSUPPRESSION AFTER METHOTREXATE, MITOZANTRONE, AND MITOMYCIN C COMBINATION CHEMOTHERAPY
SiR,—Correspondence" about myelosuppression associated with the methotrexate, mitozantrone, and mitomycin C (3M) cytotoxic combination for treatment of disseminated breast cancer" prompted analysis of updated information from 97 patients (500 courses) treated so far. In only 6 % of patients (1 % of courses) did the white-blood-cell count fall below 1 x 109/1 and in 25% of patients (6% of courses) it fell below 2 x 109/1. Blood counts were measured on day 21 unless intermediate counts were indicated for patients more at risk of bone marrow suppression because of bone marrow, hepatic, or renal dysfunction. In patients who had intermediate counts, the nadir of suppression was around day 12, and in no patient was there treatment-related septicaemia. Thrombocytopenia was rare; only 6% of patients had a platelet count below 50 x 1O9/l and in none did the count fall below 20 x 109/1. Disseminated breast cancer is probably not curable with the cytotoxic drugs available at present. We have therefore been looking for an effective combination of drugs with few side-effects providing useful palliative therapy. Mitomycin C, mitozantrone, and methotrexate were chosen because as single agents they are effective against breast cancer and all have relatively low and different subjective toxicity. Our original protocol specified an intravenous dosage schedule, based on the single agent data, of mitomycin C 8 mg/m2 every 6 weeks, mitozantrone 8 mg/m2 every 3 weeks, and methotrexate 35 mg/m2 every 3 weeks, with dose modification according to bone marrow, and renal dysfunction. Dosages were further reduced for
hepatic,
CHEMOTHERAPY FREE SURVIVAL
SIR,-Cancer chemotherapy end points are difficult to define and difficult to measure. One that is frequently used is disease-free interval (or disease-free survival). To state that a patient is disease-free should mean that the patient is free of disease. Perhapsa better phrase would be symptom-free, in the absence of X-ray or laboratory changes. The phraseology then becomes cumbersome but anything less is obfuscation. The purpose of these end points is usually to assess the response of patients to chemotherapy. Unfortunately, many of these patients are not symptom-free and the price that has to be paid for remaining "disease-free" is extreme toxicity. Indeed, the late American Senator Hubert Humphrey described cytotoxic therapy as "bottled death". This indictment is less true today, especially with the advent of endocrine-related drugs. Nonetheless, if oncologists insist on using the expression disease-free survival in a group of patients under treatment, I suggest it be contrasted with the phrase chemotherapy-free survival more
in the controls. Department of Oncology, Queen’s University of Belfast, Whitla Medical Building, Belfast BT9 7BL
SIDNEY LOWRY
HYPERTROPHIC CARDIOMYOPATHY ASSOCIATED WITH HEREDITARY SPHEROCYTOSIS IN THREE GENERATIONS OF ONE FAMILY
SIR,-Hypertrophic cardiomyopathy (HCMP) is a common disorder characterised by hypertrophy and fibre disarray. HCMP may be at least two diseases including heritable and sporadic forms. Echocardiographic studies show an autosomal dominant pattern of inheritance in familial cases.12 HCMP may be associated with congenital heart disease and several genetic disorders such as Friedreich’s ataxia, lentiginosis, and Noonan syndrome.3-5 HCMP may be linked with HLA but the data are equivocal. .1,7
starting on nebulised budesonide. He has been off oral steroids for 6 months and now no longer takes theophylline. When we first saw him he was on the 50th percentile for height and weight but his face looked puffy and his parents said he had been gaining weight rapidly. Since taking budesonide he is growing along the 10th percentile, which his parents say is his normal body build. This case has demonstrated the possibility of controlling an infant with severe, steroid-dependent asthma by means of the twice daily inhalation of nebulised budesonide. It has been possible to wean him off both oral prednisone and slow-release theophylline. We have now started treating a further three children, aged 19, 31, and 83 months, with nebulised budesonide. All three had been receiving single-dose alternate-morning prednisone 15-30 mg and all were weaned off the oral steroid within 4 weeks and theophylline within 2 months. We thank and for their
mnr
Values for for 24 h.
plasma cortisol and
IIVYI
growth
I
hormone measured
hourly
suspension of beclomethasone dipropionate administered through a nebuliser during tidal breathing for infants with severe airways obstruction.l-3 The lack of a clear benefit from this nebulised preparation-in contrast to the generally excellent response to the use of metered dose inhalers in older children-may have been related to the low drug concentration used (50 ug/ml), though a higher dose would have required a larger volume and much longer treatment times. Budesonide resembles beclomethasone dipropionate clinically and a suspension-in high concentration (1 mg/ml) has been prepared. We report the use of budesonide in an infant with severe, steroid-dependent asthma. At age 9 months a previously healthy boy began to have mild attacks of wheezing about once a month. The attacks worsened and at the age of 16 months he was admitted to hospital and then transferred to intensive care, where he was treated with bronchodilator drugs, aminophylline, and steroids. His condition improved but he continued to require steroids and was admitted twice more over the next 3 months. Severe breathlessness and wheeze persisted despite prednisone up to 40 mg daily. At age 19 months he was transferred to our unit. His condition deteriorated despite intravenous aminophylline and hydrocortisone, inhaled salbutamol, and intravenous isoprenaline (later, salbutamol). Because of exhaustion and a PCOz of 55 mm Hg he was put on a ventilator. He was extubated after 48 h and he was then gradually weaned onto slow-release theophylline, alternate morning oral prednisone, and regular inhalations of nebulised salbutamol. Out of hospital he continued to require large doses of prednisone, often given daily because of wheeze and breathlessness. On admission at age 21 months we decided to try nebulised budesonide as an alternative to high doses prednisone. 1 mg budesonide (1 ml suspension) was given twice daily through a Hudson nebuliser and open face mask powered by a compressor. 55 % of the drug was removed over the 5 min needed to complete the inhalation. He remained on theophylline and also inhaled nebulised salbutamol as needed. His condition was subsequently much improved and the prednisone dose was down to 5 mg every other morning 1 month later. The supply of budesonide then ran out temporarily and his prednisone requirement rose immediately. 2 weeks later he was back on budesonide and he was weaned off all oral prednisone 2122 months after that. He remained in excellent health with only the occasional use of inhaled salbutamol, though he took slow-release
theophylline as a precaution. 3 months after the last dose of oral prednisone the boy was admitted for adrenal function studies (figure). The 24 h integrated cortisol was 148 nmol/1 (5-3 ug/dl) (normal value in young adults
Draco/Astra, Sweden, for supplies of budesonide suspension help and encouragement.
Departments of Paediatrics and Endocnnology and Metabolism, Hadassah University Hospital, Jerusalem 91240, Israel
S. GODFREY A. AVITAL A. ROSLER A. MANDELBERG K. UWYYED
1. Storr J, Lenney CA, Lenney W. Nebulised beclomethasone dipropionate in preschool asthma. Arch Dis Child 1986; 61: 270-73 2. Webb MSC, Milner AD, Hiller EJ, Henry RL. Nebulised beclomethasone dipropionate suspension. Arch Dis Child 1986; 61: 1108-10. 3. Maayan C, Itzhaki T, Bar-Yishay E, Gross S, Tal A, Godfrey S. The functional response of infants with persistent wheezing to nebulised beclomethasone dipropionate Pediatr Pulmonol 1986; 2: 9-14 4. Zadik Z, De Lacerda L, De Carmargo AH, Hamilton BP, Migeon CJ, Kowarski AA. A comparative study of urinary hydroxycorticosteroids, urinary free cortisol and the integrated concentration of plasma cortisol. J Clin Endocrinol Metab 1980; 51: 1099-101. 5. Zadik Z, Chalew SA, Raiti S, Kowarski A. Do short children secrete insufficient growth hormone? Pediatrics 1985; 76: 355-60.
LOW FREQUENCY OF SLOW DEBRISOQUINE HYDROXYLATION IN A NATIVE CHINESE POPULATION
SIR,-Several genetic polymorphisms of drug oxidation have been established and ethnic differences in drug metabolism are widely known. The debrisoquine/sparteine type is the most studied polymorphism.1 The oriental group excreted less 4-hydroxydebrisoquine but more debrisoquine than the Caucasian group, and the frequency of debrisoquine hydroxylation deficiency was about 30% in Chinese subjects, mostly first or second generation immigrants from Hong Kong.2,3 In contrast, Nakamura et al4 found no poor metaboliser of desbrisoquine in 100 Japanese volunteers. It seems that the frequency of the poor metaboliser phenotype of debrisoquine hydroxylation varies in Far Eastern
population groups. We have studied 269 unrelated, randomly selected, native, normal Chinese volunteers (144 males) from 23 provinces and cities. All volunteers had had no recent illness, were receiving no drug, had no abnormalities on physical examinations, and no biochemical evidence of hepatic or renal dysfunction. Urine was voided immediately before an oral dose of 10 mg debrisoquine sulfate and was collected for the next 6 h. The concentrations of debrisoquine and 4-hydroxydebrisoquine were determined by gas
chromatography.s The frequency distribution of the logarithmically transformed data was bimodal (figure). The values of log metabolic ratio (MR) ranged from -0-68 to 1 63 (MR ranged from 0-21 to 43). Individuals could be phenotyped as either extensive metabolisers or as poor metabolisers with an MR of 10 or 12. Our findings showed that the frequency of the poor metaboliser phenotype of debrisoquine hydroxylation was about 0-7%. Mean recoveries of debrisoquine and 4-hydroxydebrisoquine in urine were 18 and 12%, respectively. Neither sex nor smoking habits affected debrisoquine hydroxylation in our population.
853
Frequency distribution of log debrisoquine/4-hydroxydebrisoquine metabolic ratio in 269 normal Chinese volunteers.
Soloan et al6 reported that the half-life of debrisoquine was 3h in extensive metabolisers in a Caucasian group. In 11of our extensive metabolisers, elimination rate constants were 0-25 and 0-28 h, half-lives were 2-78 and 2-73 h, and the times to reach the average maximum excretion rate were 1’67 and 1 35 for debrisoquine and 4-hydroxydebrisoquine, respectively. We thank the Chinese Council of Natural Sciences for support.
Department of Pharmacology, Beijing Medical University, Baijing, China
YA-CHING LOU LIU YING
Department of Clinical Pharmacology,
L. BERTILSSON F. SJOQVIST
Karolinska Institute, Huddinge, Sweden
patients in remission receiving maintenance therapy and for patients with evidence of myelotoxicity. The average dosages actually given were mitomycin C 6-3mg/m2, mitozantrone 6-2 mg/m2, and methotrexate 28-7 mg/m2. The dosages for the first two courses were mitomycin C 6-6 6 mg/m, mitozantrone 6’4mg/m, and methotrexate 29-9mg/m2; and by the fifth course, for those patients in remission, the dosages had been reduced to mitomycin C 5-3 3 mg/m2, mitozantrone 5-5 mg/m2, and methotrexate 26-3 mg/m2 with no evidence of loss of remission. Analysis of response showed no relation to drug dosages, indicating that a ceiling of activity had been achieved within this range. There was no significant association between dosages of any drugs and myelotoxicity, indicating that other factors, such as dose reduction for maintenance, prevailed. Significant subjective toxicity included nausea in only 28% of patients, vomiting in 12 %, alopecia in 5%, and stomatitis in 11 %. Apart from the three weekly outpatient visits for injections, most patients were able to benefit from symptomatic relief of tumour symptoms, with virtually no treatment toxicity. We have found the 3M combination to be effective palliative therapy for treatment of disseminated breast cancer, 60% of patients achieving objective remission. The severe myelosuppression reported by others probably relates to excessive dosages used in patients with compromised liver, renal, or bone marrow function. These circumstances should be be undertaken. Royal Marsden Hospital, Sutton, Surrey SM2 5PT
anticipated and dose modification should TREVOR J. POWLES SUSAN ASHLEY
A, Goodman A, Dougherty S, Ashford R Myelotoxicity of methotrexate, mitozantrone, and mitomycin C for treatment of advanced breast cancer. Lancet 1987; 1.915. 2. Jodrell DI, Iveson TJ, Smith IE. Myelosuppression after methotrexate, mitozantrone, and mitomycin C. Lancet 1978; i: 1211. 3. Morton AR, Anderson H, Howell A Myelosuppression after methotrexate, mitozantrone, and mitomycin C. Lancet 1987; i: 1494. 4. Powles TJ, Ashley SE, Forgeson GV, et al. Treatment of advanced breast cancer with mitomycin C, mitozantrone and methotrexate (3M) compared to micristine, anthracyclin and cyclophosphamide In: Bonadonna G, ed. Clinical progress with mitozantrone. London. Royal Society of Medicine Services, 1987: 1-7. 1. Marks
1. Eichelbaum M.
Polymorphic oxidation of debrisoquine and sparteine. In: Kalow W, Coedde HW, Agarwal DP, eds. Ethnic differences in reactions to drugs and xenobiotics. New York: Alan R Liss, 1986: 157-67. (Prog Clin Biol Res; vol 24.) 2. Kalow W. Ethnic differences m drug metabolism. Clin Pharmacokinet 1982; 7: 373-400. 3. Kalow W. Pharmacoanthropology: Drug metabolism. Fed Proc 1984, 43: 2326-31 4. Nakamura K, et al. Interethnic differences in genetic polymorphism of debnsoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Chn Pharmacol Ther 1985; 38: 402-08. 5. Lennard MS, et al. Determination of debrisoquine and its 4-hydroxy-metabolite in biological fluids by gas chromatography with flame-isonization and nitro-selective detection. J Chromatogr 1977; 133: 161-66. 6. Soloan TP, et al. Genetically determined oxidation capacity and the disposition of debrisoquine. Br J Clin Pharmacol 1983; 15: 443-50.
MYELOSUPPRESSION AFTER METHOTREXATE, MITOZANTRONE, AND MITOMYCIN C COMBINATION CHEMOTHERAPY
SiR,—Correspondence" about myelosuppression associated with the methotrexate, mitozantrone, and mitomycin C (3M) cytotoxic combination for treatment of disseminated breast cancer" prompted analysis of updated information from 97 patients (500 courses) treated so far. In only 6 % of patients (1 % of courses) did the white-blood-cell count fall below 1 x 109/1 and in 25% of patients (6% of courses) it fell below 2 x 109/1. Blood counts were measured on day 21 unless intermediate counts were indicated for patients more at risk of bone marrow suppression because of bone marrow, hepatic, or renal dysfunction. In patients who had intermediate counts, the nadir of suppression was around day 12, and in no patient was there treatment-related septicaemia. Thrombocytopenia was rare; only 6% of patients had a platelet count below 50 x 1O9/l and in none did the count fall below 20 x 109/1. Disseminated breast cancer is probably not curable with the cytotoxic drugs available at present. We have therefore been looking for an effective combination of drugs with few side-effects providing useful palliative therapy. Mitomycin C, mitozantrone, and methotrexate were chosen because as single agents they are effective against breast cancer and all have relatively low and different subjective toxicity. Our original protocol specified an intravenous dosage schedule, based on the single agent data, of mitomycin C 8 mg/m2 every 6 weeks, mitozantrone 8 mg/m2 every 3 weeks, and methotrexate 35 mg/m2 every 3 weeks, with dose modification according to bone marrow, and renal dysfunction. Dosages were further reduced for
hepatic,
CHEMOTHERAPY FREE SURVIVAL
SIR,-Cancer chemotherapy end points are difficult to define and difficult to measure. One that is frequently used is disease-free interval (or disease-free survival). To state that a patient is disease-free should mean that the patient is free of disease. Perhapsa better phrase would be symptom-free, in the absence of X-ray or laboratory changes. The phraseology then becomes cumbersome but anything less is obfuscation. The purpose of these end points is usually to assess the response of patients to chemotherapy. Unfortunately, many of these patients are not symptom-free and the price that has to be paid for remaining "disease-free" is extreme toxicity. Indeed, the late American Senator Hubert Humphrey described cytotoxic therapy as "bottled death". This indictment is less true today, especially with the advent of endocrine-related drugs. Nonetheless, if oncologists insist on using the expression disease-free survival in a group of patients under treatment, I suggest it be contrasted with the phrase chemotherapy-free survival more
in the controls. Department of Oncology, Queen’s University of Belfast, Whitla Medical Building, Belfast BT9 7BL
SIDNEY LOWRY
HYPERTROPHIC CARDIOMYOPATHY ASSOCIATED WITH HEREDITARY SPHEROCYTOSIS IN THREE GENERATIONS OF ONE FAMILY
SIR,-Hypertrophic cardiomyopathy (HCMP) is a common disorder characterised by hypertrophy and fibre disarray. HCMP may be at least two diseases including heritable and sporadic forms. Echocardiographic studies show an autosomal dominant pattern of inheritance in familial cases.12 HCMP may be associated with congenital heart disease and several genetic disorders such as Friedreich’s ataxia, lentiginosis, and Noonan syndrome.3-5 HCMP may be linked with HLA but the data are equivocal. .1,7