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MYELOSUPPRESSION AFTER METHOTREXATE, MITOZANTRONE, AND MITOMYCIN C COMBINATION CHEMOTHERAPY
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
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