- Email: [email protected]
Is radiation nephropathy caused by yttrium-90?
CORRESPONDENCE
4
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Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14: 7–17. Kirkwood JM, Manola J, Ibrahim J, Sondak VK, Ernstoff MS. Pooled analysis of four ECOG/intergroup trials of high-dose interferon alfa-2b (HDI) in 1916 patients with high-risk resected cutaneous melanoma. Proc ASCO 2001; 20: 350a.
Is radiation nephropathy caused by yttrium-90? Sir—Eric Cohen and colleagues (Sept 29, p 1102)1 point to a major dilemma of internal yttrium-90 radioimmunotherapy. Unfortunately, they make some misleading points that need clarification, given that this treatment option is increasingly offered at many sites in various countries. First, whereas in most internal radiotherapies myelosuppression is the dose-limiting factor, in radionuclide treatments using peptides labelled with radiometals, such as 90Y, actinic nephrotoxic effects seem to be the doselimiting factor. 90Y-labelled monoclonal antibodies, which may have only a negligible renal pathway, present with no radiation nephropathy, albeit being a radiation by 90Y. Second, Cohen and colleagues state that, in the report by Moll and colleagues,2 in cases of renal failure as a consequence of 90Y-labelled DOTA-D(DOTATOC) Phe1-Tyr3-octreotide therapies, total doses of 90Y have ranged from 666 MBq/m2 to 892 MBq/m2. However, in that report, the mean normalised cumulative dose was 6119·8 MBq/m2 (SD 1346·8) of 90Ylabelled DOTATOC. This dose was administered in divided intravenous doses every 6 weeks. Furthermore, in Moll and colleagues’ report one of the major messages is that patients treated with high-dose 90Ylabelled DOTATOC internal radiotherapy (ie, with a cumulative dose >7400 MBq/m2) are at high risk of developing severe renal failure caused by thrombotic microangiopathic lesions. However, Cybulla and colleagues3 have shown that the upper limit of 7400 MBq/m2 can be even lower in long-term observations.3 We agree that renal toxic effects of 90 Y-labelled peptide treatment are substantial, and deserve close scrutiny by institutional review boards and ethics committees and regulatory authorities. However, attention should also be drawn to the undoubted benefits of this treatment in patients who are untreatable by other conventional methods.
*Andreas Otte, Stefan M Weiner, Markus Cybulla *Obere Lachen 10, D-79110 Freiburg, Germany; and Department of Internal Medicine, University Hospital Freiburg (e-mail: [email protected]) 1
2
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Cohen EP, Moulder JE, Robbins ME. Radiation nephropathy caused by yttrium 90. Lancet 2001; 358: 1102–03. Moll S, Nickeleit V, Mueller-Brand J, Brunner FP, Maecke HR, Mihatsch MJ. A new cause of renal thrombotic microangiopathy: yttrium 90-DOTATOC internal radiotherapy. Am J Kidney Dis 2001; 37: 847–51. Cybulla M, Weiner SM, Otte A. End-stage renal disease after treatment with 90YDOTATOC. Eur J Nucl Med 2001; 28: 1552–54.
Authors’ reply Sir—Andreas Otte and colleagues rightly point out that the kidney injury associated with 90Y-labelled octreotide is not due to radioimmunotherapy or 90Y, but internal radionuclide radiotherapy. The radiation nephropathy associated with 90Y-labelled octreotide treatment is dependent on the b emission of the isotope in conjunction with the pharmacokinetics and clearance pathway of the octreotide. Similar radiation nephropathy could be caused by other combinations of radionuclide and biological carrier. A complex interplay of radionuclide dose, the pharmacokinetics and clearance pathways of the carrier, and half-life of the isotope determine the nephrotoxic effects of a radiopharmaceutical agent. Thus, although the total dose of radionuclide (in MBq/kg) is unquestionably important, the distribution and excretion of the radiopharmaceutical agent determines whether that radioactivity reaches the kidneys; and the half-life and type of the radioisotope determine the renal dose during that distribution and excretion. The total dose of any radiopharmaceutical agent is important, but is not the critical safety issue. Safety is dependent on the absorbed dose to the kidney and, to a lesser extent, the temporal rate and organ distribution of that dose. The complex interplay of pharmacokinetics, excretion pathways, and radioactivity half-life must be taken into account when considering 90Ylabelled octreotide, or any other radiopharmaceutical agent. We argue that theoretical calculations of absorbed organ dose (in this case renal dose in Gy), or even in-vivo measurements of that dose, are needed to assess properly the risk of nephrotoxic effects for any new therapeutic radiopharmaceutical agent.
Low socioeconomic status and coronary artery disease Sir—Sonia Anand and colleagues (Oct 6, p 1147)1 report a populationbased study among people of Aboriginal and European ancestry in Canada. They note an association between living in poverty and high rates of cardiovascular disease (CVD) and CVD risk factors. Their findings are supported by another study, in which the workers showed that living in disadvantaged neighbourhoods is associated with increased incidence of coronary heart disease.2 Mediating mechanisms involve established vascular risk factors and alternative factors, both of which may be linked to the risk of cardiovascular disease. Therefore, people with low socioeconomic status have significantly higher rates of smoking, glucose intolerance, obesity, abdominal obesity, and substantially higher concentrations of fibrinogen, and plasminogen activator inhibitor-1. We want to add another mediating factor possibly contributing to the association between low socioeconomic status and risk of CVD. Susceptibility to infections increases with low social status, advancing age, and risk behaviours, such as cigarette smoking and heavy drinking.3 Moreover, living in poverty is associated with exposure to different sources of chronic infections.4 Growing evidence shows that inflammation plays an important role in atherogenesis. Data on an association between chronic infections and general atherosclerosis are evolving.5 Our data from 218 patients support this hypothesis. We tested these patients referred for coronary angiography for seromarkers of six infections—hepatitis A-virus, Chlamydia pneumoniae, Helicobacter pylori, herpes simplex virus, and influenza types A and B. Patients who were seropositive for more than four of these six pathogens had a significantly higher prevalence of coronary artery disease (p=0·02). Seroepidemiological association between coronary heart disease and infectious agents such as C pneumoniae, herpes simplex virus, or cytomegalovirus has so far been documented in several studies done in different countries.5 Thus, inflammation due to chronic infections may contribute to the effects of low socioeconomic status and living in poverty on cardiovascular risk.
*Eric P Cohen, John E Moulder
*Johann W Auer, Robert Berent, Bernd C Eber
Departments of *Medicine and Radiation Oncology, Froedtert Hospital, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Department of Cardiology and Intensive Care, General Hospital Wels A-4600 Wels, Austria (e-mail: [email protected])
THE LANCET • Vol 359 • March 16, 2002 • www.thelancet.com
979
For personal use. Only reproduce with permission from The Lancet Publishing Group.
4
5
Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14: 7–17. Kirkwood JM, Manola J, Ibrahim J, Sondak VK, Ernstoff MS. Pooled analysis of four ECOG/intergroup trials of high-dose interferon alfa-2b (HDI) in 1916 patients with high-risk resected cutaneous melanoma. Proc ASCO 2001; 20: 350a.
Is radiation nephropathy caused by yttrium-90? Sir—Eric Cohen and colleagues (Sept 29, p 1102)1 point to a major dilemma of internal yttrium-90 radioimmunotherapy. Unfortunately, they make some misleading points that need clarification, given that this treatment option is increasingly offered at many sites in various countries. First, whereas in most internal radiotherapies myelosuppression is the dose-limiting factor, in radionuclide treatments using peptides labelled with radiometals, such as 90Y, actinic nephrotoxic effects seem to be the doselimiting factor. 90Y-labelled monoclonal antibodies, which may have only a negligible renal pathway, present with no radiation nephropathy, albeit being a radiation by 90Y. Second, Cohen and colleagues state that, in the report by Moll and colleagues,2 in cases of renal failure as a consequence of 90Y-labelled DOTA-D(DOTATOC) Phe1-Tyr3-octreotide therapies, total doses of 90Y have ranged from 666 MBq/m2 to 892 MBq/m2. However, in that report, the mean normalised cumulative dose was 6119·8 MBq/m2 (SD 1346·8) of 90Ylabelled DOTATOC. This dose was administered in divided intravenous doses every 6 weeks. Furthermore, in Moll and colleagues’ report one of the major messages is that patients treated with high-dose 90Ylabelled DOTATOC internal radiotherapy (ie, with a cumulative dose >7400 MBq/m2) are at high risk of developing severe renal failure caused by thrombotic microangiopathic lesions. However, Cybulla and colleagues3 have shown that the upper limit of 7400 MBq/m2 can be even lower in long-term observations.3 We agree that renal toxic effects of 90 Y-labelled peptide treatment are substantial, and deserve close scrutiny by institutional review boards and ethics committees and regulatory authorities. However, attention should also be drawn to the undoubted benefits of this treatment in patients who are untreatable by other conventional methods.
*Andreas Otte, Stefan M Weiner, Markus Cybulla *Obere Lachen 10, D-79110 Freiburg, Germany; and Department of Internal Medicine, University Hospital Freiburg (e-mail: [email protected]) 1
2
3
Cohen EP, Moulder JE, Robbins ME. Radiation nephropathy caused by yttrium 90. Lancet 2001; 358: 1102–03. Moll S, Nickeleit V, Mueller-Brand J, Brunner FP, Maecke HR, Mihatsch MJ. A new cause of renal thrombotic microangiopathy: yttrium 90-DOTATOC internal radiotherapy. Am J Kidney Dis 2001; 37: 847–51. Cybulla M, Weiner SM, Otte A. End-stage renal disease after treatment with 90YDOTATOC. Eur J Nucl Med 2001; 28: 1552–54.
Authors’ reply Sir—Andreas Otte and colleagues rightly point out that the kidney injury associated with 90Y-labelled octreotide is not due to radioimmunotherapy or 90Y, but internal radionuclide radiotherapy. The radiation nephropathy associated with 90Y-labelled octreotide treatment is dependent on the b emission of the isotope in conjunction with the pharmacokinetics and clearance pathway of the octreotide. Similar radiation nephropathy could be caused by other combinations of radionuclide and biological carrier. A complex interplay of radionuclide dose, the pharmacokinetics and clearance pathways of the carrier, and half-life of the isotope determine the nephrotoxic effects of a radiopharmaceutical agent. Thus, although the total dose of radionuclide (in MBq/kg) is unquestionably important, the distribution and excretion of the radiopharmaceutical agent determines whether that radioactivity reaches the kidneys; and the half-life and type of the radioisotope determine the renal dose during that distribution and excretion. The total dose of any radiopharmaceutical agent is important, but is not the critical safety issue. Safety is dependent on the absorbed dose to the kidney and, to a lesser extent, the temporal rate and organ distribution of that dose. The complex interplay of pharmacokinetics, excretion pathways, and radioactivity half-life must be taken into account when considering 90Ylabelled octreotide, or any other radiopharmaceutical agent. We argue that theoretical calculations of absorbed organ dose (in this case renal dose in Gy), or even in-vivo measurements of that dose, are needed to assess properly the risk of nephrotoxic effects for any new therapeutic radiopharmaceutical agent.
Low socioeconomic status and coronary artery disease Sir—Sonia Anand and colleagues (Oct 6, p 1147)1 report a populationbased study among people of Aboriginal and European ancestry in Canada. They note an association between living in poverty and high rates of cardiovascular disease (CVD) and CVD risk factors. Their findings are supported by another study, in which the workers showed that living in disadvantaged neighbourhoods is associated with increased incidence of coronary heart disease.2 Mediating mechanisms involve established vascular risk factors and alternative factors, both of which may be linked to the risk of cardiovascular disease. Therefore, people with low socioeconomic status have significantly higher rates of smoking, glucose intolerance, obesity, abdominal obesity, and substantially higher concentrations of fibrinogen, and plasminogen activator inhibitor-1. We want to add another mediating factor possibly contributing to the association between low socioeconomic status and risk of CVD. Susceptibility to infections increases with low social status, advancing age, and risk behaviours, such as cigarette smoking and heavy drinking.3 Moreover, living in poverty is associated with exposure to different sources of chronic infections.4 Growing evidence shows that inflammation plays an important role in atherogenesis. Data on an association between chronic infections and general atherosclerosis are evolving.5 Our data from 218 patients support this hypothesis. We tested these patients referred for coronary angiography for seromarkers of six infections—hepatitis A-virus, Chlamydia pneumoniae, Helicobacter pylori, herpes simplex virus, and influenza types A and B. Patients who were seropositive for more than four of these six pathogens had a significantly higher prevalence of coronary artery disease (p=0·02). Seroepidemiological association between coronary heart disease and infectious agents such as C pneumoniae, herpes simplex virus, or cytomegalovirus has so far been documented in several studies done in different countries.5 Thus, inflammation due to chronic infections may contribute to the effects of low socioeconomic status and living in poverty on cardiovascular risk.
*Eric P Cohen, John E Moulder
*Johann W Auer, Robert Berent, Bernd C Eber
Departments of *Medicine and Radiation Oncology, Froedtert Hospital, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Department of Cardiology and Intensive Care, General Hospital Wels A-4600 Wels, Austria (e-mail: [email protected])
THE LANCET • Vol 359 • March 16, 2002 • www.thelancet.com
979
For personal use. Only reproduce with permission from The Lancet Publishing Group.