1315 the 1«-hydroxylation of vitamin D is mineralisation. Since la-OHD can induce an
not
necessary for
a
improvement of
normal bone
renal
osteo-
after
being hydroxylated by the liver, as your editorial states, this drug should be considered not a pharmacological panacea but, and only if activated, a selective drug
dystrophy only
for selected bone disease. Furthermore, D.H.T., stereochemically similar to la-OHD is just as safe, is not feedback regulated, has a short half-life, and is cheaper. DIEGO BRANCACCIO CELESTINA GALMOZZI Division of Nephrology and Dialysis, STEFANO CASATI Ospedale Policlinico, CLAUDIO PONTICELLI 20122 Milan, Italy
SYSTOLIC TIME INTERVAL TO PREDICT DOXORUBICIN CARDIOTOXICITY
S;R,—Dr Johnson and colleagues (May 13, p. 1006) ask whether further doxorubicin (’Adriamycin’) can be given at a later date to patients with hepatocellular carcinoma, who have responded initially to this agent, but have reached the recommended maximum total dose of 550 mg/m2. As a result of previous reports of congestive heart-failure occurring when the drug had been reinstituted’ they advise alternative therapy. A grave disadvantage of these anthracycline antibiotics is the production of cardiotoxicity at low total dosage. In monitoring doxorubicin cardiotoxicity we find measurement of systolic time interval (S.T.I.) very helpful and report here a patient with acute myeloblastic leukaemia (A.M.L.) in whom the reintroduction of doxorubicin after 26 months resulted in myocardial dysfunction which was detected early and treated success-
fully.
30 mg/m2 on days 5, 6, and 7 for daunorubicin. S.T.I., E.C.G., and chest X-ray were monitored. The ratio of the pre-ejection period to the left-ventricular ejection-time (P.E.P,L.V.E.T.), E.C.G., and chest X-ray were normal before reinduction chemotherapy. After the first course of doxorubicin the P.E.P./L.v.E.T. increased by 0-08 but it gradually returned to near normal (figure). After the second course the P.E.P./L.v.E.T. increased progressively to 0-612 weeks after the last injection of doxoru-3 bicin, a value indicating severe left-ventricular dysfunction. At that time, the patient had shortness of breath and palpitations but E.c.G. and chest X-ray were normal. It was decided, on s.T.l. and clinical findings, to prescribe digitalis and this was followed by a remarkable improvement in exercise tolerance and general condition. His S.T.I. fell towards normal but is still abnormal 7 months after the last dose of doxorubicin. The patient is now in full hxmatological remission. There is a high risk of anthracycline cardiomypathy in patients who have received a total cumulative dose of more than 550 mg/m2 if doxorubicin is reinstituted, even more than 2 years after the last injection of the drug.’ However, we were able to detect cardiac dysfunction at an early stage in our patient by monitoring changes in his S.T.I. The S.T.I. is simple to measure and permits myocardial dysfunction to be detected at a stage when conventional treatment is effective.4,5 It seems justifiable to reintroduce doxorubicin in the treatment of patients with malignant disease with poor prognosis, provided that a sensitive method of early detection of cardiotoxicity is
available. of Hæmatology, Welsh National School of Medicine,
Department
University Hospital of Wales, Cardiff CF4 4XW
S. A. D. AL-ISMAIL
J. A. WHITTAKER
This 38-year-old man was seen in October, 1974. A diagnosis of A.M.L. was established by bone-marrow examination and he RADIONUCLEOTIDE EJECTION FRACTION AND PREDICTION OF DOXORUBICIN CARDIOTOXICITY
Changes in P.E.P./L.V.E.T. ratio in relation to cumulative dose of anthracyclines and reinduction courses with doxorubicin. daunorubicin 1-35 mg/kg intravenously and cytaramg/kg 12-hourly for 5 days. The patient entered full haematological remission after four courses and was put on maintenance chemotherapy every 4 weeks with cytarabine and daunorubicin (later doxorubicin). When the total cumulative dose of the anthracycline antibiotic reached 600 mg/m2, further maintenance chemotherapy was with cytosine and thioguanine. There were no clinical, electrocardiographic, or X-ray changes suggestive of cardiac dysfunction. Maintenance chemotherapy was stopped after 2 years of uninterrupted complete remission. The patient relapsed 8 months after the cessation of maintenance chemotherapy. Reinduction was similar to the TAD protocol of Gale and Cline2 with substitution of doxorubicin was
given
bine 1
1. O’Bryan, R. M., Baker, L. H., Gottlieb, J. E Cancer, 1977, 39, 1940. 2. Gale, R. P., Cline, M. J. Lancet, 1977, i, 497.
SIR,-No generally accepted method is available for predicting doxorubicin (’Adriamycin’) induced cardiomyopathy. This irreversible and often fatal complication prevents the longterm use of this effective agent in many patients with malignant disease. There is a sharp increase in the frequency of this complication when the cumulative dose of adriamycin exceeds 550 mg/m2.6 Lower total doses have been proposed for patients with prior cardiac irradiation or patients on cyclophosphamide.s However, not all patients exceeding 550 mg/m2 get this complication, and such a dose limit may deny the drug to patients who could tolerate additional therapy with benefit. Elderly patients with hypertension or ischxmic heart-disease are likely to develop adriamycin cardiomyopathy at lower total doses.s Intractable heart-failure may be the first sign of this cardiomyopathy. Changes in electrocardiograph (E.C.G.) tracing or on chest X-ray are late developments indicative of severe damage and thus of poor predictive value. Systolic time intervals have been proposed for monitoring decreasing ventricular function but doubt has been cast on the reliability of this method. 10 For several months we have been assessing the cumulative effects of adriamycin by serial measurement of left-ventricular ejection fraction (L.v.E.F.) by an isotope "first pass" methodlo 3. Weissler, A. M. New Engl. J. Med. 1977, 296, 321. 4. Rinehard, J., Lewis, R., Balcerzak, S. Ann. intern. Med. 1974, 81, 475. 5. Christakis, J., Lewis, R., Balcerzak, S. Proc. Am. Asso. Cancer Res. 1976, 6.
17, 276A. Lefrak, E. A., Pitha, J., Rosenheim, S., Gottlieb, J.
A. Cancer, 1973,
32,
302. 7. Merril, J.,
Greco, F. A., Zimbler, H., Brereton, H. D., Lamberg, J D., Pomeroy, T. C. Ann. intern. Med. 1975, 82, 122. 8. Minow, R. A., Benjamin, R. S., Gottlieb, J. A. Cancer Chemother Rep 1975, 6, 195. 9. Rinehart, J. J., Lewis, R. P., Balcerzak, S. P. Ann. intern. Med. 1974, 81,
475. 10. Schelbert, H. R., Verba, J. W., Johnson, A. D., Brock, G. W., Alazraki, N. P., Rose, F. J., Ashburn, W. L. Circulation, 1975, 51, 902.
not
necessary for
a
improvement of
normal bone
renal
osteo-
after
being hydroxylated by the liver, as your editorial states, this drug should be considered not a pharmacological panacea but, and only if activated, a selective drug
dystrophy only
for selected bone disease. Furthermore, D.H.T., stereochemically similar to la-OHD is just as safe, is not feedback regulated, has a short half-life, and is cheaper. DIEGO BRANCACCIO CELESTINA GALMOZZI Division of Nephrology and Dialysis, STEFANO CASATI Ospedale Policlinico, CLAUDIO PONTICELLI 20122 Milan, Italy
SYSTOLIC TIME INTERVAL TO PREDICT DOXORUBICIN CARDIOTOXICITY
S;R,—Dr Johnson and colleagues (May 13, p. 1006) ask whether further doxorubicin (’Adriamycin’) can be given at a later date to patients with hepatocellular carcinoma, who have responded initially to this agent, but have reached the recommended maximum total dose of 550 mg/m2. As a result of previous reports of congestive heart-failure occurring when the drug had been reinstituted’ they advise alternative therapy. A grave disadvantage of these anthracycline antibiotics is the production of cardiotoxicity at low total dosage. In monitoring doxorubicin cardiotoxicity we find measurement of systolic time interval (S.T.I.) very helpful and report here a patient with acute myeloblastic leukaemia (A.M.L.) in whom the reintroduction of doxorubicin after 26 months resulted in myocardial dysfunction which was detected early and treated success-
fully.
30 mg/m2 on days 5, 6, and 7 for daunorubicin. S.T.I., E.C.G., and chest X-ray were monitored. The ratio of the pre-ejection period to the left-ventricular ejection-time (P.E.P,L.V.E.T.), E.C.G., and chest X-ray were normal before reinduction chemotherapy. After the first course of doxorubicin the P.E.P./L.v.E.T. increased by 0-08 but it gradually returned to near normal (figure). After the second course the P.E.P./L.v.E.T. increased progressively to 0-612 weeks after the last injection of doxoru-3 bicin, a value indicating severe left-ventricular dysfunction. At that time, the patient had shortness of breath and palpitations but E.c.G. and chest X-ray were normal. It was decided, on s.T.l. and clinical findings, to prescribe digitalis and this was followed by a remarkable improvement in exercise tolerance and general condition. His S.T.I. fell towards normal but is still abnormal 7 months after the last dose of doxorubicin. The patient is now in full hxmatological remission. There is a high risk of anthracycline cardiomypathy in patients who have received a total cumulative dose of more than 550 mg/m2 if doxorubicin is reinstituted, even more than 2 years after the last injection of the drug.’ However, we were able to detect cardiac dysfunction at an early stage in our patient by monitoring changes in his S.T.I. The S.T.I. is simple to measure and permits myocardial dysfunction to be detected at a stage when conventional treatment is effective.4,5 It seems justifiable to reintroduce doxorubicin in the treatment of patients with malignant disease with poor prognosis, provided that a sensitive method of early detection of cardiotoxicity is
available. of Hæmatology, Welsh National School of Medicine,
Department
University Hospital of Wales, Cardiff CF4 4XW
S. A. D. AL-ISMAIL
J. A. WHITTAKER
This 38-year-old man was seen in October, 1974. A diagnosis of A.M.L. was established by bone-marrow examination and he RADIONUCLEOTIDE EJECTION FRACTION AND PREDICTION OF DOXORUBICIN CARDIOTOXICITY
Changes in P.E.P./L.V.E.T. ratio in relation to cumulative dose of anthracyclines and reinduction courses with doxorubicin. daunorubicin 1-35 mg/kg intravenously and cytaramg/kg 12-hourly for 5 days. The patient entered full haematological remission after four courses and was put on maintenance chemotherapy every 4 weeks with cytarabine and daunorubicin (later doxorubicin). When the total cumulative dose of the anthracycline antibiotic reached 600 mg/m2, further maintenance chemotherapy was with cytosine and thioguanine. There were no clinical, electrocardiographic, or X-ray changes suggestive of cardiac dysfunction. Maintenance chemotherapy was stopped after 2 years of uninterrupted complete remission. The patient relapsed 8 months after the cessation of maintenance chemotherapy. Reinduction was similar to the TAD protocol of Gale and Cline2 with substitution of doxorubicin was
given
bine 1
1. O’Bryan, R. M., Baker, L. H., Gottlieb, J. E Cancer, 1977, 39, 1940. 2. Gale, R. P., Cline, M. J. Lancet, 1977, i, 497.
SIR,-No generally accepted method is available for predicting doxorubicin (’Adriamycin’) induced cardiomyopathy. This irreversible and often fatal complication prevents the longterm use of this effective agent in many patients with malignant disease. There is a sharp increase in the frequency of this complication when the cumulative dose of adriamycin exceeds 550 mg/m2.6 Lower total doses have been proposed for patients with prior cardiac irradiation or patients on cyclophosphamide.s However, not all patients exceeding 550 mg/m2 get this complication, and such a dose limit may deny the drug to patients who could tolerate additional therapy with benefit. Elderly patients with hypertension or ischxmic heart-disease are likely to develop adriamycin cardiomyopathy at lower total doses.s Intractable heart-failure may be the first sign of this cardiomyopathy. Changes in electrocardiograph (E.C.G.) tracing or on chest X-ray are late developments indicative of severe damage and thus of poor predictive value. Systolic time intervals have been proposed for monitoring decreasing ventricular function but doubt has been cast on the reliability of this method. 10 For several months we have been assessing the cumulative effects of adriamycin by serial measurement of left-ventricular ejection fraction (L.v.E.F.) by an isotope "first pass" methodlo 3. Weissler, A. M. New Engl. J. Med. 1977, 296, 321. 4. Rinehard, J., Lewis, R., Balcerzak, S. Ann. intern. Med. 1974, 81, 475. 5. Christakis, J., Lewis, R., Balcerzak, S. Proc. Am. Asso. Cancer Res. 1976, 6.
17, 276A. Lefrak, E. A., Pitha, J., Rosenheim, S., Gottlieb, J.
A. Cancer, 1973,
32,
302. 7. Merril, J.,
Greco, F. A., Zimbler, H., Brereton, H. D., Lamberg, J D., Pomeroy, T. C. Ann. intern. Med. 1975, 82, 122. 8. Minow, R. A., Benjamin, R. S., Gottlieb, J. A. Cancer Chemother Rep 1975, 6, 195. 9. Rinehart, J. J., Lewis, R. P., Balcerzak, S. P. Ann. intern. Med. 1974, 81,
475. 10. Schelbert, H. R., Verba, J. W., Johnson, A. D., Brock, G. W., Alazraki, N. P., Rose, F. J., Ashburn, W. L. Circulation, 1975, 51, 902.
