- Email: [email protected]
Success of clinical trials in childhood Wilms' tumour around the world
Comment
Science Photo Library
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
specific condition, such as diabetes, asthma, or arthritis. In today’s Lancet, Stanton Newton and colleagues found that such interventions which focus on these conditions do more good than harm at reasonable cost. However, they add, as authors always seem to do, that more research is needed. All people with diabetes share something in common, although common biological factors become increasingly diverse as we understand more about the molecular biology of disease. But can all people with diabetes be educated as a single group? One thing all diabetic people have in common is frequent contact with health-care providers and the risks such contact entails. But how much more do diabetic people have in common? When health-care workers
promote self-management, it is an intervention, just as prescribing drugs and doing operations are interventions. When the evidence shows “effectiveness”—ie, the intervention does more good than harm—in a group of patients, we should not assume the result is equally valid for all individuals. The process of individualisation remains at the heart of clinical practice and is the primary task of the clinician. The job of the clinician is to work from a common core of knowledge or a guideline and to individualise care. There are three aspects of individualisation. First, tell the patient the evidence about their condition (eg, the presence of risk factors or other diseases). Second, having done that, allow the patient to reflect on the options presented and relate those options to the values he or she places on benefit and harm. The third aspect of individualisation, perhaps the most difficult and perhaps the one that should be dealt with first, is to individualise the style of consultation according to the preferences of the patient. This recently recognised aspect of individualisation is probably the most important of the three. All these tasks have to be set in the context of a consultation in which patients’ expectations are rapidly increasing. When patients want more information and more involvement without longer medical consultations being possible, decision aids for patients of one sort or another4 will inevitably, and quite correctly, become as much a part of clinical practice as the stethoscope and the prescription pad.
J A Muir Gray UK National Screening Committee, Institute of Health Sciences, Oxford OX3 7LF, UK I declare that I have no conflict of interest. 1 2 3 4
Holman H. Chronic disease—the need for a new clinical education. JAMA 2004; 292: 1057–59. Coulter A. The autonomous patient. London: Nuffield Trust, 2002. Gray JAM. The resourceful patient. Oxford: e-Rosetta Press, 2002. O’Connor AM, Rostom A, Fiset V, et al. Decision aids for patients facing health treatment and screening decisions: systematic review. BMJ 1999; 319: 731–34.
Success of clinical trials in childhood Wilms’ tumour around the world See Lancet 2004; 364: 1229–35
1468
The treatment of Wilms’ tumour (nephroblastoma) is one of the success stories of modern paediatric oncology, with overall survival now over 90% with relatively simple diagnostic and treatment strategies. However, over 80% of the world’s children with this disease have much poorer chances of survival because of limited access to appropriate specialist care. We believe that resource-adapted therapy could be readily implemented in many countries, with
better organisation and coordination of existing services. The recommended therapeutic approach would need to take account of the disease stage at which patients commonly present, and the relative merits of two philosophically opposed approaches to the management of Wilms’ tumour that have been practised in the developed world for over 40 years.1,2 Both approaches use two main risk factors for treatment stratification: tumour stage and www.thelancet.com Vol 364 October 23, 2004
Comment
www.thelancet.com Vol 364 October 23, 2004
investigations proved that single-dose rather than fractionated administration of actinomycin D and doxorubicin was as effective and more resource-efficient. Studies by the UK Children’s Cancer Study Group5 (UKCCSG) showed that vincristine alone, rather than vincristine and actinomycin D, was sufficient to cure most patients with stage I, favourable histology tumours. With either approach, stage I tumours receive minimum therapy with only two drugs with low potential for late effects, whereas stage III tumours are treated with both anthracyclines and radiotherapy with their potential for late sequelae of cardiomyopathy, growth abnormalities, and second primary cancers.6–8 The UKCCSG recently completed a randomised trial9 comparing the impact of the SIOP and NWTSG approaches on stage distribution in operable localised Wilms’ tumours in the same population of patients. The results of this trial, so far published only in abstract form, show a more favourable tumour-stage distribution and a reduction in overall burden of therapy after elective use of preoperative chemotherapy, which also reduced surgical complications. No trial of the treatment of Wilms’ tumour should be evaluated without considering the impact on therapy for the whole group of patients: in particular, the proportion of patients exposed to anthracyclines and/or radiotherapy. Both the SIOP and NWTSG investigators report that about
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Science Photo Library
histological subtype. However, the definition of these factors differs somewhat according to the initial management, because they can only be determined fully after nephrectomy to remove the tumorous kidney. J de Kraker et al3 recently reported the results of their latest clinical trial, SIOP 93-01, showing the successful further reduction of postoperative chemotherapy for children with stage I intermediate risk and anaplastic Wilms’ tumour from 18 to only 4 weeks, with no decrease in event-free survival (91·4% vs 88·8%, not statistically significant). This finding means that such tumours can now be “cured” by nephrectomy and a total of as little as 8 weeks of chemotherapy with only two drugs (vincristine and actinomycin D) that have little risk of acute or long-term side-effects. Investigators belonging to the International Society of Paediatric Oncology (SIOP) pioneered the concept of pretreatment of renal tumours before nephrectomy with the aim of making surgery possible and safer.2 Through successive trials they showed that surgical complications, especially tumour-rupture rates, were reduced and a more favourable tumour-stage distribution was found at delayed nephrectomy, leading to less overall burden of therapy. Their standard preoperative treatment is now chemotherapy for 4 weeks with vincristine and actinomycin D or for 6 weeks with the addition of doxorubicin for metastatic tumours. The intensity of postoperative treatment, including the need for doxorubicin and radiotherapy, is stratified according to tumour stage and histological response to initial chemotherapy. The contrasting approach has been followed by the National Wilms Tumor Study Group (NWTSG) of North America since their first study in 1969. The NWTSG decided that upfront surgery was mandatory to define the uncorrupted stage and histopathology. This approach ensured that children with non-malignant conditions were not given inappropriate cytotoxic treatment, that clear-cell sarcoma and rhabdoid tumours of the kidney could be distinguished, an important minority that were not Wilms’ tumour, and that virgin histopathological and stage variables, uncorrupted by chemotherapy or radiotherapy, could be determined. In a series of carefully planned and logical trials the NWTSG found that radiotherapy and doxorubicin could be safely omitted for favourable histology stage I and II (60% of all patients). Similarly, for stage III, favourable histology, radiotherapy could be reduced from 20 Gy to 10·8 Gy. Patients with lung metastases retained a good chance of survival with only 150 mg/m2 of doxorubicin plus pulmonary irradiation at 12 Gy. In Brazil, de Camargo et al4 showed the NWTS approach was feasible in the well equipped centres of a developing country and while overall results were not as good as those in North America, they successfully increased the cure rate from 40% to 70–80% over 10 years. These and the NWTSG
Scanning electron micrograph of Wilms’ tumour cells
1469
Comment
60% of their patients with localised tumours are treated successfully with only two drugs. The current SIOP Wilms’ Tumour 2001 trial is asking a randomised treatmentreduction question about the need for anthracylines in the postoperative treatment of selected stage II and III tumours with the use of additional histological risk groups defined on the surviving cell-type after preoperative chemotherapy.10,11 For patients with lung metastases at diagnosis, around 70% disease-free survival is expected. The SIOP group uses a higher cumulative dose of doxorubicin (250 mg/m2) but avoids lung irradiation in those—the majority—with rapidly responding lung metastases, whereas NWTSG uses a lower dose of anthracycline (150 mg/m2) but recommends lung irradiation (12 Gy) for all. Is it worth risking failure of front-line therapy in order to avoid treatment that might cause permanent side-effects? Since tumour stage and histology are readily and rapidly determined, and the overall prognosis is so good, we believe that is the case. In the future, however, risk-adapted therapy must use the growing knowledge of Wilms’ tumour molecular pathology. The NWTSG 5 study chose to exploit molecular markers measured at initial diagnosis to predict outcome. While the presence of allele loss at specified loci did indeed identify a higher risk group, the test was incompletely sensitive and specific so that the majority of relapsing patients still came from the so-called “favourable histology” group with no evidence of allele loss (Grundy P, Chair, Renal Tumors Committee, Children’s Oncology Group, North America). However, such molecular analyses are difficult to organise and expensive. The SIOP approach provides the opportunity to correlate molecular changes with the more easily available histological response to preoperative chemotherapy, which may be as informative for predicting outcome.12 What is to be learned from these studies, not only for countries of the privileged world but also for the poorly resourced countries whose children are just as susceptible or, in the case of Afro-Caribbean populations, even more susceptible to Wilms’ tumour?13 The best buy for all these patients is the SIOP response-adapted approach with preoperative chemotherapy and delayed nephrectomy followed by risk-stratified postoperative chemotherapy and, if available, radiotherapy where necessary. Why? Partly because so many children present with advanced initially inoperable disease, but also because cure at least cost is the maxim of paediatric oncologists worldwide. Costs can be medical, psychosocial, and economic. Medical costs are reduced if patients are cured first-time round. The efficacy and side-effects of initial treatment must be balanced against the potential for late sequelae and risk of relapse, whose treatment is necessarily more burdensome. Psychosocial cost reduction includes lessening the trauma for the child and family, and reducing the family turmoil 1470
that childhood cancer brings. The economic savings for national health services are self-evident. If treatment can be reduced without increasing the relapse rate, health dollars are saved in the short term, as they are in the longer term if late effects are reduced. None of these conclusions could be drawn without the multicentre trials piloted by pioneering investigators of the NWTSG from 1969 and SIOP from 1970. They laid out the necessary ingredients for success, not only by providing the expertise for multidisciplinary teams (paediatric oncology, radiotherapy, surgery, pathology) but also by realising before most other doctors that randomised trials were the way to go. Their foresight is a cause for celebration.
*K Pritchard-Jones, J Pritchard Institute of Cancer Research/Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK (KP-J); and Royal Hospital for Sick Children, Edinburgh, UK (JP) [email protected] We declare that we have no conflict of interest. 1
2
3
4
5
6
7
8
9
10
11
12
13
Green DM, Breslow NE, Beckwith JB, et al. Effect of duration of treatment on treatment outcome and cost of treatment for Wilms tumour: a report from the National Wilms Tumor Study Group. J Clin Oncol 1998; 16: 3744–51. Tournade MF, Com-Nougue C, de Kraker, et al. Optimal duration of preoperative chemotherapy in unilateral and nonmetastatic Wilms tumour in children older than 6 months: results of the ninth International Society of Paediatric Oncology Wilms tumour trial and study. J Clin Oncol 2001; 19: 488–500. de Kraker J, Graf N, van Tinteren H, for the International Society of Paediatric Oncology Nephroblastoma Trial Committee. Reduction of postoperative chemotherapy in children with stage I intermediate-risk and anaplastic Wilms’ tumour (SIOP 93-01 trial): a randomised controlled trial. Lancet 2004; 364: 1229–35. De Camargo B, Franco EL. A randomised clinical trial of single-dose versus fractionated dose dactinomycin in the treatment of Wilms’ tumour: results after extended follow up. Brazilian Wilms’ Tumour Study Group. Cancer 1994; 73: 3081–86. Pritchard-Jones K, Kelsey A, Vujanic G, et al. Older age is an adverse prognostic factor in stage I favourable histology Wilms tumour treated with vincristine mono-chemotherapy: a UK Children’s Cancer Study Group Study. J Clin Oncol 2003; 21: 3269–75. Green DM, Grigoriev YA, Nan B, et al. Congestive heart failure after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study group. J Clin Oncol 2001; 19: 1926–34. Breslow NE, Takashima JR, Whitton JA, Moksness J, D’Angio G, Green DM. Second malignant neoplasms following treatment for Wilms tumour: a report from the National Wilms Tumor Study Group. J Clin Oncol 1995; 13: 1851–59. Carli M, Frascella E, Tournade MR, et al. Second malignant neoplasms in patients treated on SIOP Wilms tumour Studies and Trials 1, 2, 5 and 6. Med Pediatr Oncol 1997; 29: 239–44. Mitchell C, Shannon R, Vujanic G, et al. The treatment of Wilms tumour: the United Kingdom Children’s Cancer Study Group Third Wilms tumour study. Med Pediatr Oncol 2003; 41: 287 (abst O119). Bergeron C, Graf N, van Tinteren H, et al. From results of SIOP nephroblastoma 93–01 study to SIOP nephroblastoma 2001 study. Med Pediatr Oncol 2003; 41: 289 (abstr O131). Vujanic GM, Sandstedt B, Harms D et al Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood. Med Pediatr Oncol 2002; 38: 79–82. Weirich A, Leuschner I, Harms D, et al. Clinical impact of histological subtypes in non-anaplastic nephroblastoma treated according to the trial and study SIOP9/GPOH. Ann Oncol 2001; 12: 311–19. Stiller CA, Parkin DM International variations in the incidence of childhood renal tumours. Br J Cancer 1990; 62: 1026–30.
www.thelancet.com Vol 364 October 23, 2004
Science Photo Library
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
specific condition, such as diabetes, asthma, or arthritis. In today’s Lancet, Stanton Newton and colleagues found that such interventions which focus on these conditions do more good than harm at reasonable cost. However, they add, as authors always seem to do, that more research is needed. All people with diabetes share something in common, although common biological factors become increasingly diverse as we understand more about the molecular biology of disease. But can all people with diabetes be educated as a single group? One thing all diabetic people have in common is frequent contact with health-care providers and the risks such contact entails. But how much more do diabetic people have in common? When health-care workers
promote self-management, it is an intervention, just as prescribing drugs and doing operations are interventions. When the evidence shows “effectiveness”—ie, the intervention does more good than harm—in a group of patients, we should not assume the result is equally valid for all individuals. The process of individualisation remains at the heart of clinical practice and is the primary task of the clinician. The job of the clinician is to work from a common core of knowledge or a guideline and to individualise care. There are three aspects of individualisation. First, tell the patient the evidence about their condition (eg, the presence of risk factors or other diseases). Second, having done that, allow the patient to reflect on the options presented and relate those options to the values he or she places on benefit and harm. The third aspect of individualisation, perhaps the most difficult and perhaps the one that should be dealt with first, is to individualise the style of consultation according to the preferences of the patient. This recently recognised aspect of individualisation is probably the most important of the three. All these tasks have to be set in the context of a consultation in which patients’ expectations are rapidly increasing. When patients want more information and more involvement without longer medical consultations being possible, decision aids for patients of one sort or another4 will inevitably, and quite correctly, become as much a part of clinical practice as the stethoscope and the prescription pad.
J A Muir Gray UK National Screening Committee, Institute of Health Sciences, Oxford OX3 7LF, UK I declare that I have no conflict of interest. 1 2 3 4
Holman H. Chronic disease—the need for a new clinical education. JAMA 2004; 292: 1057–59. Coulter A. The autonomous patient. London: Nuffield Trust, 2002. Gray JAM. The resourceful patient. Oxford: e-Rosetta Press, 2002. O’Connor AM, Rostom A, Fiset V, et al. Decision aids for patients facing health treatment and screening decisions: systematic review. BMJ 1999; 319: 731–34.
Success of clinical trials in childhood Wilms’ tumour around the world See Lancet 2004; 364: 1229–35
1468
The treatment of Wilms’ tumour (nephroblastoma) is one of the success stories of modern paediatric oncology, with overall survival now over 90% with relatively simple diagnostic and treatment strategies. However, over 80% of the world’s children with this disease have much poorer chances of survival because of limited access to appropriate specialist care. We believe that resource-adapted therapy could be readily implemented in many countries, with
better organisation and coordination of existing services. The recommended therapeutic approach would need to take account of the disease stage at which patients commonly present, and the relative merits of two philosophically opposed approaches to the management of Wilms’ tumour that have been practised in the developed world for over 40 years.1,2 Both approaches use two main risk factors for treatment stratification: tumour stage and www.thelancet.com Vol 364 October 23, 2004
Comment
www.thelancet.com Vol 364 October 23, 2004
investigations proved that single-dose rather than fractionated administration of actinomycin D and doxorubicin was as effective and more resource-efficient. Studies by the UK Children’s Cancer Study Group5 (UKCCSG) showed that vincristine alone, rather than vincristine and actinomycin D, was sufficient to cure most patients with stage I, favourable histology tumours. With either approach, stage I tumours receive minimum therapy with only two drugs with low potential for late effects, whereas stage III tumours are treated with both anthracyclines and radiotherapy with their potential for late sequelae of cardiomyopathy, growth abnormalities, and second primary cancers.6–8 The UKCCSG recently completed a randomised trial9 comparing the impact of the SIOP and NWTSG approaches on stage distribution in operable localised Wilms’ tumours in the same population of patients. The results of this trial, so far published only in abstract form, show a more favourable tumour-stage distribution and a reduction in overall burden of therapy after elective use of preoperative chemotherapy, which also reduced surgical complications. No trial of the treatment of Wilms’ tumour should be evaluated without considering the impact on therapy for the whole group of patients: in particular, the proportion of patients exposed to anthracyclines and/or radiotherapy. Both the SIOP and NWTSG investigators report that about
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Science Photo Library
histological subtype. However, the definition of these factors differs somewhat according to the initial management, because they can only be determined fully after nephrectomy to remove the tumorous kidney. J de Kraker et al3 recently reported the results of their latest clinical trial, SIOP 93-01, showing the successful further reduction of postoperative chemotherapy for children with stage I intermediate risk and anaplastic Wilms’ tumour from 18 to only 4 weeks, with no decrease in event-free survival (91·4% vs 88·8%, not statistically significant). This finding means that such tumours can now be “cured” by nephrectomy and a total of as little as 8 weeks of chemotherapy with only two drugs (vincristine and actinomycin D) that have little risk of acute or long-term side-effects. Investigators belonging to the International Society of Paediatric Oncology (SIOP) pioneered the concept of pretreatment of renal tumours before nephrectomy with the aim of making surgery possible and safer.2 Through successive trials they showed that surgical complications, especially tumour-rupture rates, were reduced and a more favourable tumour-stage distribution was found at delayed nephrectomy, leading to less overall burden of therapy. Their standard preoperative treatment is now chemotherapy for 4 weeks with vincristine and actinomycin D or for 6 weeks with the addition of doxorubicin for metastatic tumours. The intensity of postoperative treatment, including the need for doxorubicin and radiotherapy, is stratified according to tumour stage and histological response to initial chemotherapy. The contrasting approach has been followed by the National Wilms Tumor Study Group (NWTSG) of North America since their first study in 1969. The NWTSG decided that upfront surgery was mandatory to define the uncorrupted stage and histopathology. This approach ensured that children with non-malignant conditions were not given inappropriate cytotoxic treatment, that clear-cell sarcoma and rhabdoid tumours of the kidney could be distinguished, an important minority that were not Wilms’ tumour, and that virgin histopathological and stage variables, uncorrupted by chemotherapy or radiotherapy, could be determined. In a series of carefully planned and logical trials the NWTSG found that radiotherapy and doxorubicin could be safely omitted for favourable histology stage I and II (60% of all patients). Similarly, for stage III, favourable histology, radiotherapy could be reduced from 20 Gy to 10·8 Gy. Patients with lung metastases retained a good chance of survival with only 150 mg/m2 of doxorubicin plus pulmonary irradiation at 12 Gy. In Brazil, de Camargo et al4 showed the NWTS approach was feasible in the well equipped centres of a developing country and while overall results were not as good as those in North America, they successfully increased the cure rate from 40% to 70–80% over 10 years. These and the NWTSG
Scanning electron micrograph of Wilms’ tumour cells
1469
Comment
60% of their patients with localised tumours are treated successfully with only two drugs. The current SIOP Wilms’ Tumour 2001 trial is asking a randomised treatmentreduction question about the need for anthracylines in the postoperative treatment of selected stage II and III tumours with the use of additional histological risk groups defined on the surviving cell-type after preoperative chemotherapy.10,11 For patients with lung metastases at diagnosis, around 70% disease-free survival is expected. The SIOP group uses a higher cumulative dose of doxorubicin (250 mg/m2) but avoids lung irradiation in those—the majority—with rapidly responding lung metastases, whereas NWTSG uses a lower dose of anthracycline (150 mg/m2) but recommends lung irradiation (12 Gy) for all. Is it worth risking failure of front-line therapy in order to avoid treatment that might cause permanent side-effects? Since tumour stage and histology are readily and rapidly determined, and the overall prognosis is so good, we believe that is the case. In the future, however, risk-adapted therapy must use the growing knowledge of Wilms’ tumour molecular pathology. The NWTSG 5 study chose to exploit molecular markers measured at initial diagnosis to predict outcome. While the presence of allele loss at specified loci did indeed identify a higher risk group, the test was incompletely sensitive and specific so that the majority of relapsing patients still came from the so-called “favourable histology” group with no evidence of allele loss (Grundy P, Chair, Renal Tumors Committee, Children’s Oncology Group, North America). However, such molecular analyses are difficult to organise and expensive. The SIOP approach provides the opportunity to correlate molecular changes with the more easily available histological response to preoperative chemotherapy, which may be as informative for predicting outcome.12 What is to be learned from these studies, not only for countries of the privileged world but also for the poorly resourced countries whose children are just as susceptible or, in the case of Afro-Caribbean populations, even more susceptible to Wilms’ tumour?13 The best buy for all these patients is the SIOP response-adapted approach with preoperative chemotherapy and delayed nephrectomy followed by risk-stratified postoperative chemotherapy and, if available, radiotherapy where necessary. Why? Partly because so many children present with advanced initially inoperable disease, but also because cure at least cost is the maxim of paediatric oncologists worldwide. Costs can be medical, psychosocial, and economic. Medical costs are reduced if patients are cured first-time round. The efficacy and side-effects of initial treatment must be balanced against the potential for late sequelae and risk of relapse, whose treatment is necessarily more burdensome. Psychosocial cost reduction includes lessening the trauma for the child and family, and reducing the family turmoil 1470
that childhood cancer brings. The economic savings for national health services are self-evident. If treatment can be reduced without increasing the relapse rate, health dollars are saved in the short term, as they are in the longer term if late effects are reduced. None of these conclusions could be drawn without the multicentre trials piloted by pioneering investigators of the NWTSG from 1969 and SIOP from 1970. They laid out the necessary ingredients for success, not only by providing the expertise for multidisciplinary teams (paediatric oncology, radiotherapy, surgery, pathology) but also by realising before most other doctors that randomised trials were the way to go. Their foresight is a cause for celebration.
*K Pritchard-Jones, J Pritchard Institute of Cancer Research/Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK (KP-J); and Royal Hospital for Sick Children, Edinburgh, UK (JP) [email protected] We declare that we have no conflict of interest. 1
2
3
4
5
6
7
8
9
10
11
12
13
Green DM, Breslow NE, Beckwith JB, et al. Effect of duration of treatment on treatment outcome and cost of treatment for Wilms tumour: a report from the National Wilms Tumor Study Group. J Clin Oncol 1998; 16: 3744–51. Tournade MF, Com-Nougue C, de Kraker, et al. Optimal duration of preoperative chemotherapy in unilateral and nonmetastatic Wilms tumour in children older than 6 months: results of the ninth International Society of Paediatric Oncology Wilms tumour trial and study. J Clin Oncol 2001; 19: 488–500. de Kraker J, Graf N, van Tinteren H, for the International Society of Paediatric Oncology Nephroblastoma Trial Committee. Reduction of postoperative chemotherapy in children with stage I intermediate-risk and anaplastic Wilms’ tumour (SIOP 93-01 trial): a randomised controlled trial. Lancet 2004; 364: 1229–35. De Camargo B, Franco EL. A randomised clinical trial of single-dose versus fractionated dose dactinomycin in the treatment of Wilms’ tumour: results after extended follow up. Brazilian Wilms’ Tumour Study Group. Cancer 1994; 73: 3081–86. Pritchard-Jones K, Kelsey A, Vujanic G, et al. Older age is an adverse prognostic factor in stage I favourable histology Wilms tumour treated with vincristine mono-chemotherapy: a UK Children’s Cancer Study Group Study. J Clin Oncol 2003; 21: 3269–75. Green DM, Grigoriev YA, Nan B, et al. Congestive heart failure after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study group. J Clin Oncol 2001; 19: 1926–34. Breslow NE, Takashima JR, Whitton JA, Moksness J, D’Angio G, Green DM. Second malignant neoplasms following treatment for Wilms tumour: a report from the National Wilms Tumor Study Group. J Clin Oncol 1995; 13: 1851–59. Carli M, Frascella E, Tournade MR, et al. Second malignant neoplasms in patients treated on SIOP Wilms tumour Studies and Trials 1, 2, 5 and 6. Med Pediatr Oncol 1997; 29: 239–44. Mitchell C, Shannon R, Vujanic G, et al. The treatment of Wilms tumour: the United Kingdom Children’s Cancer Study Group Third Wilms tumour study. Med Pediatr Oncol 2003; 41: 287 (abst O119). Bergeron C, Graf N, van Tinteren H, et al. From results of SIOP nephroblastoma 93–01 study to SIOP nephroblastoma 2001 study. Med Pediatr Oncol 2003; 41: 289 (abstr O131). Vujanic GM, Sandstedt B, Harms D et al Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood. Med Pediatr Oncol 2002; 38: 79–82. Weirich A, Leuschner I, Harms D, et al. Clinical impact of histological subtypes in non-anaplastic nephroblastoma treated according to the trial and study SIOP9/GPOH. Ann Oncol 2001; 12: 311–19. Stiller CA, Parkin DM International variations in the incidence of childhood renal tumours. Br J Cancer 1990; 62: 1026–30.
www.thelancet.com Vol 364 October 23, 2004