1099
Hazards of
gallium for Paget’s disease of bone
SIR,-We appreciate Dr Altmann and Dr Cunningham’s concern (Feb 24, p 477) about possible long-term adverse effects in patients with Paget’s disease of bone treated with 100 mg/m2 daily of intravenous gallium nitrate for 5 days that we reported (Jan 13, p 72). This dose is conservative compared with that used for hypercalcaemia of malignancy (up to 1000 mg/m2 single dose1 or 200 mg/m2 daily for 5 days2). We have given 100 mg/m2 daily for 5 days to eleven patients, and more than a year later have no evidence of adverse effects. As with any new agent, adverse effects may become apparent when the drug is used in a large population. Altmann and Cunningham suggest that gallium may have adverse effects similar to those of aluminium. The toxicity of aluminium has been widely investigated and was reported as early as 1921.3 We are well aware of the controversy about the relation between aluminium and Alzheimer’s disease and its accumulation in the brains of patients undergoing haemodialysis for renal failure.4 In contrast to our patients with normal renal function, uraemic individuals show increased toxicity from compounds that are excreted by the kidneys, and therefore extrapolations between these two groups are not
appropriate. A recent report in which aluminium was measured (by means of dispersive X-ray microprobe and flameless atomic absorption spectrophotometry) in the brains of subjects who died with Alzheimer’s disease failed to confirm the relation between aluminium and Alzheimer’s disease.5 We are aware that gallium is a group IIIA metal in the periodic chart6 and are familiar with its proximity to aluminium. Altmann and Cunningham’s idea that the periodic chart is used to predict clinical toxicity may well have merit. However, examination of the toxicities of other elements based on their position in the periodic chart, including gold and silver, sodium and lithium, lithium and potassium, zinc and cadmium, calcium and strontium, fluorine and chlorine, suggests that this idea may be an oversimplification. To examine possible toxicities resulting from treatment with gallium, we studied 200 Sprague-Dawley rats randomly divided into equal groups to receive either gallium or normal saline. Treated animals received subcutaneous (sc) injections of gallium nitrate (30 mg/kg), followed after 1 week by 10 mg/kg sc per week for up to 22 weeks. Controls received weekly injections of an equal volume of sc normal saline. A bioavailability study in rats with indwelling jugular catheters verified complete absorption of gallium nitrate following sc administration. Preliminary toxicology studies were done on energy
brain, eye, femur, kidneys, adrenals, heart, liver, spleen, pancreas, lung, thyroid, and parathyroid. All animals examined (treated and untreated) had lymphoid hyperplasia in the lung. Gallium-treated animals had an increased frequency of interstitial pneumonia and an increased frequency and severity of nephropathy. Brains were examined histologically in two sections-temporal cortex, basal ganglia, and thalamus; and cerebellum and medulla-and no abnormalities were noted. Dr Warrell (p 477) also expresses concern about the dose we used. He claims that 100 mg/m2 daily for 5 days may be "excessive" in patients with Paget’s disease of bone. In his studies Warrell has used doses of 100 mg/m2 daily of intravenous gallium for 7 days.7 An ideal dose has not yet been established. Warrell further expresses dissatisfaction that only three of thirty-three of our references were related to the clinical use of gallium. We could not refer to other such publications since ours was the first. Furthermore, we did not refer to Warrell’s three abstracts, or our four (all published in 1989), because the Vancouver style specifically states that references to abstracts should be avoided.8 We hope that Warrell has noticed in particular our reference to H. C. Dudley,9,lO a pioneer of disposition and metabolism studies of gallium. Department of Pharmacology,
College
of
Medicine, Ohio State University, Columbus, OH 43210, USA
VELIMIR MATKOVIC GLEN APSELOFF DALE SHEPARD NICHOLAS GERBER
1. Krakoff
IH, Newmann RA, Goldberg RS Clinical toxicologic and pharmacologic studies of gallium nitrate. Cancer 1979; 44: 1722-27. 2. Warrell RP, Israel R, Frisone M, Snyder T, Gaynor JJ, Bockman RS. Gallium nitrate for acute treatment of cancer related hypercalcaemia. Ann Intern Med 1988; 108: 669-74. 3. Spofforth J. Case of aluminium poisoning. Lancet 1921; i: 1301. 4. Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy syndrome: possible aluminium intoxication. N Engl J Med 1976; 294: 184-88. 5. Jacobs RW, Duone T, Jones RE, Trapp GA, Scheibel AB. A reexamination of aluminium in Alzheimer’s disease: analysis by energy dispersive X-ray microprobe and flameless atomic absorption spectrophotometry. Can J Neurol Sci 1989; 16: 498-503. 6. Matkovic V, Apseloff G, Shepard DR, Gerber N Use of gallium to treat Paget’s disease of bone: a pilot study. Lancet 1990; 335: 72-75. 7. Warrell RP, Bockman RS, Bosco B, Levme B, Lane J. Biochemical effects of gallium nitrate in Paget’s disease of bone. Clin Res 1984; 37: 463A. 8. The Vancouver style. Lancet 1979; i: 428-30. 9. Dudley HC, Maddox GE. Deposition of radio gallium (Ga72) in skeletal tissues. J Pharmacol Exp Ther 1949; 95: 224-27. 10. Dudley HC, Marrer HH. Studies of the metabolism of gallium, III: deposition in and clearance from bone. Pharmacol J Exp Ther 1952; 106: 129-34
Success of
non-surgical management of ectopic pregnancy
SiR,—The management of ectopic pregnancy by local instillation of
prostaglandins’ and glucose2 appears to be an alternative to conventional operative treatment. We propose another conservative non-surgical management-ie, monitoring of human chorionic gonadotropin (hCG), in the hope of a spontaneous resolution of tubal pregnancy. Over a year 102 patients had an ectopic pregnancy in our institute. 33 were recruited according to the following criteria: tubal ampullary pregnancy, desire for further pregnancy, serum hCG of 2500 IU/1 or less, no sign of rupture or acute bleeding, and a tubal diameter of less than 4-5 cm verified laparoscopically. The project was approved by the local ethical committee and all patients gave Patients were admitted and serum hCG was If hCG decreased for 5 days the patient was daily. discharged and observed as an outpatient until hCG was below 10 IU/1. The outcome was successful in 27 patients (82%). The 6 other patients and the remaining 69 patients underwent laparotomy. Altogether, more than a quarter of all ectopic pregnancies (27/102, 26%) ended in spontaneous regression and in these cases our policy of non-interference sufficed. We will test the clinical significance of these promising findings in a prospective randomised trial with other conservative methods.
informed measured
consent.
Department of Obstetrics and Gynaecology, and Central Laboratory, University Central Hospital of Turku, SF-20520 Turku, Finland
J. I. MÄKINEN A. K. KIVIJÄRVI K. M. A. IRJALA
1. Lindblom B, Hahlin M, Kallfelt B, Hamberger L. Local prostaglandin F2 injections for termination of ectopic pregnancy. Lancet 1987; i. 776-77. 2. Lang P, Weiss PAM, Mayer HO. Local application of hyperosmolar glucose solution in
tubal pregnancy. Lancet 1989;
i:
922-23.
Adjuvant chemo-endocrine therapy in postmenopausal women with breast cancer and axillary-node metastases Mild and colleagues (March 3, p 541) claim that adjuvant treatment with tamoxifen 20 mg daily plus cyclophosphamide, methotrexate, and 5-fluorouracil (Tam-CMF) "leads to only a preliminary increase in disease-free survival which does not persist up to 5 years after the breast surgery". This clinical evidence was based on a randomised comparison of three treatment options-Tam alone, CMF alone, and Tam-CMF-in 100 patients. The effect of adjuvant systemic therapy is modest and a trial as small as that described by Mikl et al is likely to miss treatment effects. In fact, a large worldwide effort is underway to identify more effective treatments by use of meta-analysis on all available randomised comparisons, and many trials of chemo-endocrine therapy are still in progress. We report data which show that this form of treatment might be useful. 463 postmenopausal women (aged 65 years or less) with breast cancer and axillary node involvement were randomly allocated to
SIR,-Dr
combined
Hazards of
gallium for Paget’s disease of bone
SIR,-We appreciate Dr Altmann and Dr Cunningham’s concern (Feb 24, p 477) about possible long-term adverse effects in patients with Paget’s disease of bone treated with 100 mg/m2 daily of intravenous gallium nitrate for 5 days that we reported (Jan 13, p 72). This dose is conservative compared with that used for hypercalcaemia of malignancy (up to 1000 mg/m2 single dose1 or 200 mg/m2 daily for 5 days2). We have given 100 mg/m2 daily for 5 days to eleven patients, and more than a year later have no evidence of adverse effects. As with any new agent, adverse effects may become apparent when the drug is used in a large population. Altmann and Cunningham suggest that gallium may have adverse effects similar to those of aluminium. The toxicity of aluminium has been widely investigated and was reported as early as 1921.3 We are well aware of the controversy about the relation between aluminium and Alzheimer’s disease and its accumulation in the brains of patients undergoing haemodialysis for renal failure.4 In contrast to our patients with normal renal function, uraemic individuals show increased toxicity from compounds that are excreted by the kidneys, and therefore extrapolations between these two groups are not
appropriate. A recent report in which aluminium was measured (by means of dispersive X-ray microprobe and flameless atomic absorption spectrophotometry) in the brains of subjects who died with Alzheimer’s disease failed to confirm the relation between aluminium and Alzheimer’s disease.5 We are aware that gallium is a group IIIA metal in the periodic chart6 and are familiar with its proximity to aluminium. Altmann and Cunningham’s idea that the periodic chart is used to predict clinical toxicity may well have merit. However, examination of the toxicities of other elements based on their position in the periodic chart, including gold and silver, sodium and lithium, lithium and potassium, zinc and cadmium, calcium and strontium, fluorine and chlorine, suggests that this idea may be an oversimplification. To examine possible toxicities resulting from treatment with gallium, we studied 200 Sprague-Dawley rats randomly divided into equal groups to receive either gallium or normal saline. Treated animals received subcutaneous (sc) injections of gallium nitrate (30 mg/kg), followed after 1 week by 10 mg/kg sc per week for up to 22 weeks. Controls received weekly injections of an equal volume of sc normal saline. A bioavailability study in rats with indwelling jugular catheters verified complete absorption of gallium nitrate following sc administration. Preliminary toxicology studies were done on energy
brain, eye, femur, kidneys, adrenals, heart, liver, spleen, pancreas, lung, thyroid, and parathyroid. All animals examined (treated and untreated) had lymphoid hyperplasia in the lung. Gallium-treated animals had an increased frequency of interstitial pneumonia and an increased frequency and severity of nephropathy. Brains were examined histologically in two sections-temporal cortex, basal ganglia, and thalamus; and cerebellum and medulla-and no abnormalities were noted. Dr Warrell (p 477) also expresses concern about the dose we used. He claims that 100 mg/m2 daily for 5 days may be "excessive" in patients with Paget’s disease of bone. In his studies Warrell has used doses of 100 mg/m2 daily of intravenous gallium for 7 days.7 An ideal dose has not yet been established. Warrell further expresses dissatisfaction that only three of thirty-three of our references were related to the clinical use of gallium. We could not refer to other such publications since ours was the first. Furthermore, we did not refer to Warrell’s three abstracts, or our four (all published in 1989), because the Vancouver style specifically states that references to abstracts should be avoided.8 We hope that Warrell has noticed in particular our reference to H. C. Dudley,9,lO a pioneer of disposition and metabolism studies of gallium. Department of Pharmacology,
College
of
Medicine, Ohio State University, Columbus, OH 43210, USA
VELIMIR MATKOVIC GLEN APSELOFF DALE SHEPARD NICHOLAS GERBER
1. Krakoff
IH, Newmann RA, Goldberg RS Clinical toxicologic and pharmacologic studies of gallium nitrate. Cancer 1979; 44: 1722-27. 2. Warrell RP, Israel R, Frisone M, Snyder T, Gaynor JJ, Bockman RS. Gallium nitrate for acute treatment of cancer related hypercalcaemia. Ann Intern Med 1988; 108: 669-74. 3. Spofforth J. Case of aluminium poisoning. Lancet 1921; i: 1301. 4. Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy syndrome: possible aluminium intoxication. N Engl J Med 1976; 294: 184-88. 5. Jacobs RW, Duone T, Jones RE, Trapp GA, Scheibel AB. A reexamination of aluminium in Alzheimer’s disease: analysis by energy dispersive X-ray microprobe and flameless atomic absorption spectrophotometry. Can J Neurol Sci 1989; 16: 498-503. 6. Matkovic V, Apseloff G, Shepard DR, Gerber N Use of gallium to treat Paget’s disease of bone: a pilot study. Lancet 1990; 335: 72-75. 7. Warrell RP, Bockman RS, Bosco B, Levme B, Lane J. Biochemical effects of gallium nitrate in Paget’s disease of bone. Clin Res 1984; 37: 463A. 8. The Vancouver style. Lancet 1979; i: 428-30. 9. Dudley HC, Maddox GE. Deposition of radio gallium (Ga72) in skeletal tissues. J Pharmacol Exp Ther 1949; 95: 224-27. 10. Dudley HC, Marrer HH. Studies of the metabolism of gallium, III: deposition in and clearance from bone. Pharmacol J Exp Ther 1952; 106: 129-34
Success of
non-surgical management of ectopic pregnancy
SiR,—The management of ectopic pregnancy by local instillation of
prostaglandins’ and glucose2 appears to be an alternative to conventional operative treatment. We propose another conservative non-surgical management-ie, monitoring of human chorionic gonadotropin (hCG), in the hope of a spontaneous resolution of tubal pregnancy. Over a year 102 patients had an ectopic pregnancy in our institute. 33 were recruited according to the following criteria: tubal ampullary pregnancy, desire for further pregnancy, serum hCG of 2500 IU/1 or less, no sign of rupture or acute bleeding, and a tubal diameter of less than 4-5 cm verified laparoscopically. The project was approved by the local ethical committee and all patients gave Patients were admitted and serum hCG was If hCG decreased for 5 days the patient was daily. discharged and observed as an outpatient until hCG was below 10 IU/1. The outcome was successful in 27 patients (82%). The 6 other patients and the remaining 69 patients underwent laparotomy. Altogether, more than a quarter of all ectopic pregnancies (27/102, 26%) ended in spontaneous regression and in these cases our policy of non-interference sufficed. We will test the clinical significance of these promising findings in a prospective randomised trial with other conservative methods.
informed measured
consent.
Department of Obstetrics and Gynaecology, and Central Laboratory, University Central Hospital of Turku, SF-20520 Turku, Finland
J. I. MÄKINEN A. K. KIVIJÄRVI K. M. A. IRJALA
1. Lindblom B, Hahlin M, Kallfelt B, Hamberger L. Local prostaglandin F2 injections for termination of ectopic pregnancy. Lancet 1987; i. 776-77. 2. Lang P, Weiss PAM, Mayer HO. Local application of hyperosmolar glucose solution in
tubal pregnancy. Lancet 1989;
i:
922-23.
Adjuvant chemo-endocrine therapy in postmenopausal women with breast cancer and axillary-node metastases Mild and colleagues (March 3, p 541) claim that adjuvant treatment with tamoxifen 20 mg daily plus cyclophosphamide, methotrexate, and 5-fluorouracil (Tam-CMF) "leads to only a preliminary increase in disease-free survival which does not persist up to 5 years after the breast surgery". This clinical evidence was based on a randomised comparison of three treatment options-Tam alone, CMF alone, and Tam-CMF-in 100 patients. The effect of adjuvant systemic therapy is modest and a trial as small as that described by Mikl et al is likely to miss treatment effects. In fact, a large worldwide effort is underway to identify more effective treatments by use of meta-analysis on all available randomised comparisons, and many trials of chemo-endocrine therapy are still in progress. We report data which show that this form of treatment might be useful. 463 postmenopausal women (aged 65 years or less) with breast cancer and axillary node involvement were randomly allocated to
SIR,-Dr
combined
