1022
patients treated with intensive chemotherapy regimens at doses used in younger patients.6 These findings indicate that such an aggressive approach to treatment is not appropriate in unselected patients older than 70 years with unfavourable non-Hodgkin lymphoma. Moreover, in elderly patients such drug toxicity may be under-reported, because elderly patients are more likely to be lost to follow-up or treated by clinicians other than oncologists for treatment-related toxicity, symptoms of chemotherapeutic toxicity may be misinterpreted as age-related, and wrongly ascribed to infectious disease. Instead of arbitrary change to a regimen designed for and tested in younger patients, EORTC has devised an intensive chemotherapy regimen specifically for elderly patients with aggressive non-Hodgkin lymphoma, in which antineoplastic agents with an acceptable toxicity in elderly patients were selected. This regimen (VMP, etoposide, mitozantrone, and prednimustine) is under evaluation, compared with the CHOP regimen (cyclophosphamide, adriamycin, vincristine, and prednisone) in a prospective EORTC lymphoma group trial. Indeed, elderly patients are particularly appropriate for evaluation of new agents or regimens because they have usually received little or no previous treatment for the condition, unlike younger patients with the same disease. concomitant cardiac
or
Discussion Treatment of elderly patients should be part of the mainstream of oncological practice. Since such practice is largely based on the results of clinical trials, whenever possible the age range of such studies should be extended or prospective studies of treatment of cancer in the elderly should be set up. The aim of good oncological practice is to
Ifosfamide in paediatric
probabilities of cure and toxicity, and chance of palliation with quality of life. Why should this not also apply to the elderly? The EORTC have set up a study group to examine strategy for cancer treatment in the elderly. A joint EORTC/National Cancer Institute meeting will be held in October, 1990, to discuss the need for studies in the elderly and to determine age criteria appropriate for all published work. At present most papers on so-called "elderly" patients are based on selected individuals, usually older than 65 but less than 75 years of age, for whom the median age is rarely reported-which means that the conclusions of such studies are largely meaningless. The same rigour should be applied to the study of elderly patients with cancer as for younger people; only then will we see strikingly reduced population mortality and improved quality of life for older patients with cancer--outcomes which are long overdue. balance
REFERENCES 1. National Cancer Institute. Annual cancer statistics update: December 8, 1986. Bethesda, Maryland: NCI, 1986.
2. Office
of
Population Censuses
Surveys. Cancer statistics
102: 218-28. 4. Samet J, Hunt WC, Key C, et al. Choice of cancer therapy varies with age of patient. JAMA 1986; 255: 3385-90. 5. Falk GL, Gwynne-Jones D, Gray JG. Efficacy of tamoxifen on the primary treatment of operable breast cancer in the high risk patient. Aust NZ J Surg 1989; 59: 543-45. 6. Tirelli U, Zagonel V, Serraino D, et al. Non-Hodgkin’s lymphomas in 137 patients aged 70 years or older: a retrospective European Organisation for Research and Treatment of Cancer lymphoma group study. J Clin Oncol 1988; 11: 1708-13.
oncology: tried
Rational chemotherapeutic practice requires a logical progression in the investigation and use of novel antineoplastic drugs. Ifosfamide is a structural analogue of cyclophosphamide; the slightly altered structure results in a similar spectrum of activity to cyclophosphamide, possibly with reduced myelotoxicity, and animal experiments indicate that it is not wholly cross-resistant with cyclophosphamide. In early clinical studies, however, severe urothelial toxicity precluded further use until mesna became available in the early 1980s. Since then, ifosfamide has been used in many studies, often at higher equivalent doses than cyclophosphamide: in terms of alkylating activity in plasma or urine, the equivalent dose of ifosfamide is 3 to 4 times that of cyclophosphamide-but alkylating activity is not equated with clinical activity.1 In a controlled study of adults with soft-tissue sarcomaifosfamide (at a dose of 5-8 g/m2 as a 24-h infusion) was compared with cyclophosphamide (1-5-2-5g/m2 as a 24-h infusion). The total response was 18% for patients given ifosfamide and 8% for those given cyclophosphamide, but when corrected for sex (women had a better prognosis) and previous chemotherapy the difference was not significant-and the types of sarcoma
and
registrations, England and Wales. 1984. London: HM Stationery Office, 1988. 3. Lipschitz DA, Goldstein S, Weksler ME, Bressler R, Neilan BA. Cancer in the elderly: basic science and clinical aspects. Ann Intern Med 1985;
but not tested?
which showed most response are rarely found in children. This is not adequate evidence for a superiority of ifosfamide over cyclophosphamide in the treatment of soft tissue sarcomas in children. In a study of treatments for Ewing’s sarcoma,3 the German Paediatric Oncology Group substituted ifosfamide for cyclophosphamide in patients considered to be at higher risk of treatment failure (from data from an earlier study). These patients fared better than those in the previous study, but they also underwent earlier surgery and the dose of ifosfamide used was higher than the equivalent dose of cyclophosphamide. Over a similar period, the French Society of Paediatric Oncology also substituted ifosfamide for cyclophosphamide in their regimen for treatment of Ewing’s sarcoma, and found no improvement in 3-year disease-free survival;4 congestive cardiac failure was observed more frequently than with cyclophosphamide, although both protocols contained similar doses of adriamycin. Flamant et al5 studied patients with ADDRESS Department of Paediatric Haematology, Royal Hospital for Sick Children, Edinburgh EH91LF, UK (P J Shaw, FRACP, T Eden, FRCPE) Correspondence to Dr P J Shaw
1023
those who achieved complete remission with chemotherapy alone (ifosfamide, vincristine, and actinomycin D [IVA]) had a 50% relapse rate,S which raised some doubts about the durability of remissions achieved with this combination, the overall results of which were no better than those achieved with vincristine,
rhabdomyosarcoma;
actinomycin D, and cyclophosphamide (VAC).6 After use of ifosfamide for treatment of patients with relapsed neuroblastoma, Kellie et all used ifosfamide as initial therapy for this tumour (ENSG IlIa): all 18 patients treated have died of relapsed or refractory disease. Although the initial response was adequate (8 patients showed some response after two courses of ifosfamide alone), when the patients went onto further therapy they did much worse than historical controls or contemporary patients treated with cisplatin and etoposide (ENSG IIlb; 40% 2-year disease-free survivaI8). The results were also worse than those obtained by Kushner et a19 with a regimen (N4SE) which includes very high doses of cyclophosphamide with adriamycin and vincristine, and low doses of some other agents. Kellie et aF suggested that, after ifosfamide treatment, patients became more resistant to other agentsas opposed to the views of Pratt et all who suggest that new agents may be tried before conventional therapy on the assumption that a short course of a new agent will not jeopardise the response to standard chemotherapy. It is possible that the effect seen by Kellie et al is confined to more chemoresistant, pleomorphic tumours such as neuroblastoma-but may also apply to related neoplasms such as brain tumours. If there is little evidence of a clear advantage of ifosfamide over cyclophosphamide, where is the evidence that it is as safe? Ifosfamide/mesna encephalopathy is much less common in children than in adults, although fatal cases have been reported ,11 but there have been several recent reports’2 " of renal tubular dysfunction associated with ifosfamide treatment. Skinner and coworkers16 also described a worrying reduction in glomerular filtration rate soon after treatment, which may interact with tubular problems such as hypophosphataemia and lead to a long-term risk of renal failure; this may be even more of a problem in patients with a single kidney, who may also show increased myelotoxicity because of slower clearance of ifosfamide. And now that the long-term risks of second malignancy are better understood, is the risk of bladder cancer likely to be increased because ifosfamide is so much more toxic to the urothelium than cyclophosphamide? Despite these questions, ifosfamide has been incorporated into several frontline protocols: for example in treatments of soft-tissue sarcoma (MMT 84s and 8919), Ewing’s sarcoma (ET-2), and Wilms’ tumour (SIOP-921). Jurgens and colleagues22 have calculated that almost half the children in West Germany with newly diagnosed cancer will receive ifosfamide as part of their initial treatment. But where are comparative trials of the efficacy of ifosfamide compared with cyclophosphamide? High-dose cyclophosphamide can be administered in a similar way to ifosfamide,9 and a similar cyclophosphamide regimen has been used successfully in Ewing’s sarcoma.23 Even before recent reports of ifosfamide toxicity, these two agents should have been properly evaluated in prospective controlled trials in which, for example, a regimen that included standard cyclophosphamide doses was compared with regimens that included high-dose cyclophosphamide or ifosfamide. There is no doubt that ifosfamide is an effective
antineoplastic agent, particularly for adults with soft-tissue sarcomas, but there have been too few studies of its efficacy in with and high-dose safety comparison cyclophosphamide. After recent reports of ifosfamiderelated toxicity, its use should be carefully reassessed, especially in paediatric oncological practice, until long-term follow-up is available for the patients already treated or the results of further comparative studies are available. By contrast, there has been considerable discussion about substitution of carboplatin for cisplatin;2425 why has this debate not arisen for substitution of ifosfamide for
cyclophosphamide? REFERENCES 1. Zalupski M, Baker LH. Ifosfamide. J Natl Cancer Inst 1988; 80: 556-66. 2. Bramwell VHC, Mouridsen HT, Santoro A, et al. Cyclophosphamide versus ifosfamide: final report of a randomised phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 1987; 23: 311-21. 3. Jurgens H, Gadner H, Gobel U, et al. Update of the cooperative Ewing’s sarcoma studies (CESS) of the German Society of Pediatric Oncology. Med Pediatr Oncol 1989; 17: 284 (abstr). 4. Zucker JM, Oberlin O, Demeocq F, et al. Ifosfamide (IFO) in Ewing’s
No benefit compared to cyclophosphamide (CYCLO) but cardiac toxicity. A report from the French Society of Pediatric Oncology (SFOP). Med Pediatr Oncol 1989; 17: 284 (abstr). 5. Flamant F, Rodary C, Rey A. Malignant mesenchymal tumors (MMT) 1984 study. 21st meeting of International Society of Paediatric Oncology. Prague, Sept 18-22, 1989: abstr 27. 6. Ruymann FB. Rhabdomyosarcoma in children and adolescents: a review. Hematol Oncol Clin North Am 1987; 1: 621-54. 7. Kellie SJ, de Kraker J, Lilleyman JS, et al. Ifosfamide in previously untreated disseminated neuroblastoma. Eur J Cancer Clin Oncol 1988; 24: 903-08. 8. Hartmann O, Pinkerton CR, Philip T, et al. Very-high-dose cisplatin and etoposide in children with untreated advanced neuroblastoma. J Clin Oncol 1988; 6: 44-50. 9. Kushner BH, Helson L. Coordinated use of sequentially escalated cyclophosphamide and cell-cycle-specific chemotherapy (N4SE protocol) for advanced neuroblastoma: experience with 100 patients. J Clin Oncol 1987; 5: 1746-51. 10. Pratt CB, Douglass EC, Etcubanas E, et al. Clinical studies of ifosfamide/mesna at St Jude Children’s Research Hospital, 1983-1988. Semin Oncol 1989; 16 (suppl 3): 51-55. 11. Verdeguer A, Castel V, Esquembre C, et al. Fatal encephalopathy with ifosfamide/mesna. Pediatr Hematol Oncol 1989: 6: 383-85. 12. Skinner R, Pearson ADJ, Price L, et al. Hypophosphataemic rickets after ifosfamide treatment in children. Br Med J 1989; 298: 1560-61. 13. Newbury-Ecob RA, Noble VW, Barbor PRH. Ifosfamide-induced Fanconi syndrome. Lancet 1989; i: 1328. 14. Caron HN, Abeling N, de Kraker J, et al. Hyperaminoaciduria, a functional index of ifosfamide-induced renal tubular dysfunction. Med Pediatr Oncol 1989; 17: 326 (abstr). 15. Navajas A, Vallo A, Labayru M, et al. Renal toxicity (Fanconi’s syndrome) due to ifosfamide therapy. Med Pediatr Oncol 1989; 17: 331 sarcoma.
more
(abstr). 16. Skinner R, Pearson ADJ, Price L, et al. Nephrotoxicity of ifosfamide. Med Pediatr Oncol 1989; 17: 333 (abstr). 17. Burk CD, Restaino I, Kaplan B, et al. Ifosfamide-induced rickets in childhood.Proc Am Soc Clin Oncol 1989; 8: 297 (abstr). 18. Jonsson OG, Buchanan GR. Renal toxicity after treatment with ifosfamide (IFX). Proc Am Soc Clin Oncol 1989; 8: 65 (abstr). 19. Stevens M, Flamant F. International Society of Paediatric Oncology: malignant mesenchymal tumours (MMT) 1989 study. 21st meeting of International Society of Paediatric Oncology. Prague, Sept 18-22, 1989. 20. Craft AW, Spooner D, Lewis I. The UKCCSG second Ewing’s tumour study (ET-2). Med Pediatr Oncol 1989; 17: 287 (abstr). 21. Carli M, Voute PA, Toumade MF, et al. Nephroblastoma clinical trial SIOP 9: preliminary report. 21st meeting of International Society of Paediatric Oncology. Prague, Sept 18-22, 1989. 22. Jurgens H, Treuner J, Winkler K, et al. Ifosfamide in pediatric malignancies. Semin Oncol 1989; 16 (suppl 3): 46-50. 23. Rosen G. The current management of malignant bone tumours. Where do we go from here? Med J Aust 1988; 148: 373-77. 24. Von Hoff DD. Whither carboplatin? A replacement for or an alternative to cisplatin? J Clin Oncol 1987; 5: 169-71. 25. Calvert AH, Horwich A, Newlands ES, et al. Carboplatin or cisplatin? Lancet 1988; ii: 577-78.
patients treated with intensive chemotherapy regimens at doses used in younger patients.6 These findings indicate that such an aggressive approach to treatment is not appropriate in unselected patients older than 70 years with unfavourable non-Hodgkin lymphoma. Moreover, in elderly patients such drug toxicity may be under-reported, because elderly patients are more likely to be lost to follow-up or treated by clinicians other than oncologists for treatment-related toxicity, symptoms of chemotherapeutic toxicity may be misinterpreted as age-related, and wrongly ascribed to infectious disease. Instead of arbitrary change to a regimen designed for and tested in younger patients, EORTC has devised an intensive chemotherapy regimen specifically for elderly patients with aggressive non-Hodgkin lymphoma, in which antineoplastic agents with an acceptable toxicity in elderly patients were selected. This regimen (VMP, etoposide, mitozantrone, and prednimustine) is under evaluation, compared with the CHOP regimen (cyclophosphamide, adriamycin, vincristine, and prednisone) in a prospective EORTC lymphoma group trial. Indeed, elderly patients are particularly appropriate for evaluation of new agents or regimens because they have usually received little or no previous treatment for the condition, unlike younger patients with the same disease. concomitant cardiac
or
Discussion Treatment of elderly patients should be part of the mainstream of oncological practice. Since such practice is largely based on the results of clinical trials, whenever possible the age range of such studies should be extended or prospective studies of treatment of cancer in the elderly should be set up. The aim of good oncological practice is to
Ifosfamide in paediatric
probabilities of cure and toxicity, and chance of palliation with quality of life. Why should this not also apply to the elderly? The EORTC have set up a study group to examine strategy for cancer treatment in the elderly. A joint EORTC/National Cancer Institute meeting will be held in October, 1990, to discuss the need for studies in the elderly and to determine age criteria appropriate for all published work. At present most papers on so-called "elderly" patients are based on selected individuals, usually older than 65 but less than 75 years of age, for whom the median age is rarely reported-which means that the conclusions of such studies are largely meaningless. The same rigour should be applied to the study of elderly patients with cancer as for younger people; only then will we see strikingly reduced population mortality and improved quality of life for older patients with cancer--outcomes which are long overdue. balance
REFERENCES 1. National Cancer Institute. Annual cancer statistics update: December 8, 1986. Bethesda, Maryland: NCI, 1986.
2. Office
of
Population Censuses
Surveys. Cancer statistics
102: 218-28. 4. Samet J, Hunt WC, Key C, et al. Choice of cancer therapy varies with age of patient. JAMA 1986; 255: 3385-90. 5. Falk GL, Gwynne-Jones D, Gray JG. Efficacy of tamoxifen on the primary treatment of operable breast cancer in the high risk patient. Aust NZ J Surg 1989; 59: 543-45. 6. Tirelli U, Zagonel V, Serraino D, et al. Non-Hodgkin’s lymphomas in 137 patients aged 70 years or older: a retrospective European Organisation for Research and Treatment of Cancer lymphoma group study. J Clin Oncol 1988; 11: 1708-13.
oncology: tried
Rational chemotherapeutic practice requires a logical progression in the investigation and use of novel antineoplastic drugs. Ifosfamide is a structural analogue of cyclophosphamide; the slightly altered structure results in a similar spectrum of activity to cyclophosphamide, possibly with reduced myelotoxicity, and animal experiments indicate that it is not wholly cross-resistant with cyclophosphamide. In early clinical studies, however, severe urothelial toxicity precluded further use until mesna became available in the early 1980s. Since then, ifosfamide has been used in many studies, often at higher equivalent doses than cyclophosphamide: in terms of alkylating activity in plasma or urine, the equivalent dose of ifosfamide is 3 to 4 times that of cyclophosphamide-but alkylating activity is not equated with clinical activity.1 In a controlled study of adults with soft-tissue sarcomaifosfamide (at a dose of 5-8 g/m2 as a 24-h infusion) was compared with cyclophosphamide (1-5-2-5g/m2 as a 24-h infusion). The total response was 18% for patients given ifosfamide and 8% for those given cyclophosphamide, but when corrected for sex (women had a better prognosis) and previous chemotherapy the difference was not significant-and the types of sarcoma
and
registrations, England and Wales. 1984. London: HM Stationery Office, 1988. 3. Lipschitz DA, Goldstein S, Weksler ME, Bressler R, Neilan BA. Cancer in the elderly: basic science and clinical aspects. Ann Intern Med 1985;
but not tested?
which showed most response are rarely found in children. This is not adequate evidence for a superiority of ifosfamide over cyclophosphamide in the treatment of soft tissue sarcomas in children. In a study of treatments for Ewing’s sarcoma,3 the German Paediatric Oncology Group substituted ifosfamide for cyclophosphamide in patients considered to be at higher risk of treatment failure (from data from an earlier study). These patients fared better than those in the previous study, but they also underwent earlier surgery and the dose of ifosfamide used was higher than the equivalent dose of cyclophosphamide. Over a similar period, the French Society of Paediatric Oncology also substituted ifosfamide for cyclophosphamide in their regimen for treatment of Ewing’s sarcoma, and found no improvement in 3-year disease-free survival;4 congestive cardiac failure was observed more frequently than with cyclophosphamide, although both protocols contained similar doses of adriamycin. Flamant et al5 studied patients with ADDRESS Department of Paediatric Haematology, Royal Hospital for Sick Children, Edinburgh EH91LF, UK (P J Shaw, FRACP, T Eden, FRCPE) Correspondence to Dr P J Shaw
1023
those who achieved complete remission with chemotherapy alone (ifosfamide, vincristine, and actinomycin D [IVA]) had a 50% relapse rate,S which raised some doubts about the durability of remissions achieved with this combination, the overall results of which were no better than those achieved with vincristine,
rhabdomyosarcoma;
actinomycin D, and cyclophosphamide (VAC).6 After use of ifosfamide for treatment of patients with relapsed neuroblastoma, Kellie et all used ifosfamide as initial therapy for this tumour (ENSG IlIa): all 18 patients treated have died of relapsed or refractory disease. Although the initial response was adequate (8 patients showed some response after two courses of ifosfamide alone), when the patients went onto further therapy they did much worse than historical controls or contemporary patients treated with cisplatin and etoposide (ENSG IIlb; 40% 2-year disease-free survivaI8). The results were also worse than those obtained by Kushner et a19 with a regimen (N4SE) which includes very high doses of cyclophosphamide with adriamycin and vincristine, and low doses of some other agents. Kellie et aF suggested that, after ifosfamide treatment, patients became more resistant to other agentsas opposed to the views of Pratt et all who suggest that new agents may be tried before conventional therapy on the assumption that a short course of a new agent will not jeopardise the response to standard chemotherapy. It is possible that the effect seen by Kellie et al is confined to more chemoresistant, pleomorphic tumours such as neuroblastoma-but may also apply to related neoplasms such as brain tumours. If there is little evidence of a clear advantage of ifosfamide over cyclophosphamide, where is the evidence that it is as safe? Ifosfamide/mesna encephalopathy is much less common in children than in adults, although fatal cases have been reported ,11 but there have been several recent reports’2 " of renal tubular dysfunction associated with ifosfamide treatment. Skinner and coworkers16 also described a worrying reduction in glomerular filtration rate soon after treatment, which may interact with tubular problems such as hypophosphataemia and lead to a long-term risk of renal failure; this may be even more of a problem in patients with a single kidney, who may also show increased myelotoxicity because of slower clearance of ifosfamide. And now that the long-term risks of second malignancy are better understood, is the risk of bladder cancer likely to be increased because ifosfamide is so much more toxic to the urothelium than cyclophosphamide? Despite these questions, ifosfamide has been incorporated into several frontline protocols: for example in treatments of soft-tissue sarcoma (MMT 84s and 8919), Ewing’s sarcoma (ET-2), and Wilms’ tumour (SIOP-921). Jurgens and colleagues22 have calculated that almost half the children in West Germany with newly diagnosed cancer will receive ifosfamide as part of their initial treatment. But where are comparative trials of the efficacy of ifosfamide compared with cyclophosphamide? High-dose cyclophosphamide can be administered in a similar way to ifosfamide,9 and a similar cyclophosphamide regimen has been used successfully in Ewing’s sarcoma.23 Even before recent reports of ifosfamide toxicity, these two agents should have been properly evaluated in prospective controlled trials in which, for example, a regimen that included standard cyclophosphamide doses was compared with regimens that included high-dose cyclophosphamide or ifosfamide. There is no doubt that ifosfamide is an effective
antineoplastic agent, particularly for adults with soft-tissue sarcomas, but there have been too few studies of its efficacy in with and high-dose safety comparison cyclophosphamide. After recent reports of ifosfamiderelated toxicity, its use should be carefully reassessed, especially in paediatric oncological practice, until long-term follow-up is available for the patients already treated or the results of further comparative studies are available. By contrast, there has been considerable discussion about substitution of carboplatin for cisplatin;2425 why has this debate not arisen for substitution of ifosfamide for
cyclophosphamide? REFERENCES 1. Zalupski M, Baker LH. Ifosfamide. J Natl Cancer Inst 1988; 80: 556-66. 2. Bramwell VHC, Mouridsen HT, Santoro A, et al. Cyclophosphamide versus ifosfamide: final report of a randomised phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 1987; 23: 311-21. 3. Jurgens H, Gadner H, Gobel U, et al. Update of the cooperative Ewing’s sarcoma studies (CESS) of the German Society of Pediatric Oncology. Med Pediatr Oncol 1989; 17: 284 (abstr). 4. Zucker JM, Oberlin O, Demeocq F, et al. Ifosfamide (IFO) in Ewing’s
No benefit compared to cyclophosphamide (CYCLO) but cardiac toxicity. A report from the French Society of Pediatric Oncology (SFOP). Med Pediatr Oncol 1989; 17: 284 (abstr). 5. Flamant F, Rodary C, Rey A. Malignant mesenchymal tumors (MMT) 1984 study. 21st meeting of International Society of Paediatric Oncology. Prague, Sept 18-22, 1989: abstr 27. 6. Ruymann FB. Rhabdomyosarcoma in children and adolescents: a review. Hematol Oncol Clin North Am 1987; 1: 621-54. 7. Kellie SJ, de Kraker J, Lilleyman JS, et al. Ifosfamide in previously untreated disseminated neuroblastoma. Eur J Cancer Clin Oncol 1988; 24: 903-08. 8. Hartmann O, Pinkerton CR, Philip T, et al. Very-high-dose cisplatin and etoposide in children with untreated advanced neuroblastoma. J Clin Oncol 1988; 6: 44-50. 9. Kushner BH, Helson L. Coordinated use of sequentially escalated cyclophosphamide and cell-cycle-specific chemotherapy (N4SE protocol) for advanced neuroblastoma: experience with 100 patients. J Clin Oncol 1987; 5: 1746-51. 10. Pratt CB, Douglass EC, Etcubanas E, et al. Clinical studies of ifosfamide/mesna at St Jude Children’s Research Hospital, 1983-1988. Semin Oncol 1989; 16 (suppl 3): 51-55. 11. Verdeguer A, Castel V, Esquembre C, et al. Fatal encephalopathy with ifosfamide/mesna. Pediatr Hematol Oncol 1989: 6: 383-85. 12. Skinner R, Pearson ADJ, Price L, et al. Hypophosphataemic rickets after ifosfamide treatment in children. Br Med J 1989; 298: 1560-61. 13. Newbury-Ecob RA, Noble VW, Barbor PRH. Ifosfamide-induced Fanconi syndrome. Lancet 1989; i: 1328. 14. Caron HN, Abeling N, de Kraker J, et al. Hyperaminoaciduria, a functional index of ifosfamide-induced renal tubular dysfunction. Med Pediatr Oncol 1989; 17: 326 (abstr). 15. Navajas A, Vallo A, Labayru M, et al. Renal toxicity (Fanconi’s syndrome) due to ifosfamide therapy. Med Pediatr Oncol 1989; 17: 331 sarcoma.
more
(abstr). 16. Skinner R, Pearson ADJ, Price L, et al. Nephrotoxicity of ifosfamide. Med Pediatr Oncol 1989; 17: 333 (abstr). 17. Burk CD, Restaino I, Kaplan B, et al. Ifosfamide-induced rickets in childhood.Proc Am Soc Clin Oncol 1989; 8: 297 (abstr). 18. Jonsson OG, Buchanan GR. Renal toxicity after treatment with ifosfamide (IFX). Proc Am Soc Clin Oncol 1989; 8: 65 (abstr). 19. Stevens M, Flamant F. International Society of Paediatric Oncology: malignant mesenchymal tumours (MMT) 1989 study. 21st meeting of International Society of Paediatric Oncology. Prague, Sept 18-22, 1989. 20. Craft AW, Spooner D, Lewis I. The UKCCSG second Ewing’s tumour study (ET-2). Med Pediatr Oncol 1989; 17: 287 (abstr). 21. Carli M, Voute PA, Toumade MF, et al. Nephroblastoma clinical trial SIOP 9: preliminary report. 21st meeting of International Society of Paediatric Oncology. Prague, Sept 18-22, 1989. 22. Jurgens H, Treuner J, Winkler K, et al. Ifosfamide in pediatric malignancies. Semin Oncol 1989; 16 (suppl 3): 46-50. 23. Rosen G. The current management of malignant bone tumours. Where do we go from here? Med J Aust 1988; 148: 373-77. 24. Von Hoff DD. Whither carboplatin? A replacement for or an alternative to cisplatin? J Clin Oncol 1987; 5: 169-71. 25. Calvert AH, Horwich A, Newlands ES, et al. Carboplatin or cisplatin? Lancet 1988; ii: 577-78.
