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Optimal Duration of Preoperative Therapy in Unilateral and Nonmetastatic Wilms’ Tumor in Children Older Than 6 Months: Results of the Ninth International Society of Pediatric Oncology Wilms’ Tumor Trial and Study

From the Institut Gustave-Roussy, Villejuif; Institut Curie and University Paris VI, Paris, France; Emma Kinderziekenhuis/Academish Medical Center, Amsterdam, the Netherlands; Division of Hematology and Oncology, Childrens’ Hospital, University of Heidelberg, Germany; Marciniak Hospital, Wroclow, Poland; Clinica Pediatrica dell’Università, Padova, Italy; and Universitätsklinik für Strahlentherapie and Biologie, Wien, Austria.

Address reprint requests to M.F. Tournade, MD, Institut Gustave-Roussy, Département de Pédiatrie, 39 Rue Camille Desmoulins, 94805 Villejuif, Cedex, France; email tournade{at}igr.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1: APPENDIX 2: REFERENCES

 
PURPOSE: To determine the optimal duration of preoperative chemotherapy to further increase the proportion of stage I tumors by comparison of two regimens in the treatment of patients older than 6 months who have unilateral Wilms’ tumor.

PATIENTS AND METHODS: Eligible patients (n = 382) initially received four weekly doses of vincristine (VCR) and two courses of actinomycin D (AMD) and were randomized either to be operated on (4-week group [n = 193]) or to receive 4 more weeks of the same chemotherapy regimen (8-week group [n = 189]). The assessment criterion was the observed percentage of stage I tumors. After surgery, patients were assigned according to tumor stage and histology to four different treatment groups: stage I and favorable histology (n = 5) were to have no further treatment (NFT); stage I and standard histology or anaplasia (n = 244), VCR and AMD for 17 weeks (AV); stages II and III and favorable or standard histology, VCR, AMD, and an anthracycline for 27 weeks (AVE) with no abdominal radiotherapy for stage II N0 disease (n = 75) or with a 15-Gy dose of abdominal irradiation (RTH) in case of stages IIN1 and III (n = 56). Anaplastic tumors staged higher than I or clear-cell sarcoma of the kidney (14), AMD, VCR, an anthracycline, and ifosfamide for 36 weeks (DEVI).

RESULTS: No advantage was found in favor of prolonged preoperative treatment. The percentages obtained for the 4-week and the 8-week groups, respectively, were as follows: stage I, 64% versus 62%; intraoperative tumor rupture rate, 1% versus 3%; 2-year EFS, 84% versus 83%; and 5-year OS, 92% versus 87%. Two-year EFS and 5-year OS rates, respectively, of the different treatment groups were as follows: NFT, 100% for both EFS and OS; AV, 88% and 93%; AVE, 84% and 88%; AVE RTH, 71% and 85%; and DEVI, 71% and 71%. The rate of abdominal recurrences in stage II N0 nonirradiated patients was 6.6%.

CONCLUSION: The 4-week schedule pre-nephrectomy chemotherapy regimen should be considered the standard treatment. Clinical trials should continue to improve the cure rate of high-risk patients and the quality of life of children with a more favorable prognosis.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1: APPENDIX 2: REFERENCES

 
THE CURE RATE attained in children with Wilms’ tumor (WT) has been improving over the years. Several multicenter trials and studies have been conducted by the International Society of Pediatric Oncology (SIOP) in Europe^1-3 and the National Wilms’ Tumor Study (NWTS) in the United States.^4-7 They have contributed to a definition of the basis for current treatment of this tumor: a multidisciplinary approach combining surgery and multidrug therapy associated, only when necessary, with radiotherapy (RTH). Treatments are given according to well-defined risk groups to decrease the frequency and the intensity of complications as well as the cost of therapy. The specific contribution of the SIOP trials and studies^2,3 was to demonstrate the role of preoperative chemotherapy in downstaging tumors to stage I.

The main objective of SIOP 9, the present study, was to determine the optimal duration of preoperative chemotherapy to further increase the rate of stage I tumors and, thus, lower the number of stages II and III tumors, which require more aggressive therapy. Two arms of preoperative chemotherapy were compared: the standard arm of 4-week duration versus a new one of 8-week duration.

With respect to postoperative and maintenance chemotherapy, the results of SIOP 6³ and NWTS II and III studies^5,6,8 provided reliable information on relevant risk groups based on stage and histologic features. Adapted therapeutic approaches were designed as follows. For stage I patients, the short vincristine (VCR) and actinomycin D (AMD) (AV) protocol, as defined in the SIOP 6 trial, was used in the SIOP 9 study. Patients with an anaplastic WT were included in this population. On the other hand, a small group of patients with a favorable histology (nephroblastoma of the multicystic type and those with fibroadenomatous structures) did not receive any therapy after surgery.

In patients with a stage II N0 tumor without unfavorable histologic features, equivalence was demonstrated in 2-year event-free survival (EFS) between the two treatment arms with or without flank RTH combined with a two-drug regimen, but the comparison failed to show either a difference in or equivalence of overall survival (OS).^3,10 However, the abdominal recurrences that occurred in children who did not receive flank RTH and the level of the 5-year survival curves (< 80%) in both arms suggest the need for more intensive postoperative and maintenance chemotherapy.

The findings of NWTS 2 and 3^5,6 in terms of drugs used, dose-intensity, EFS, and local recurrence rate were the basis for the design of the SIOP 9 VCR, AMD, and anthracycline (AVE) protocol for treatment of patients with stage II N0 disease. The adjunction of an anthracycline and a more intensive AV protocol compared with SIOP 6 was to be evaluated in patients who did not receive RTH.

The results observed in SIOP 6³ in favor of the doxorubicin regimen in patients with stages II N1 and III disease with a standard histology were the reason that the same three-drug AVE protocol was used, as in patients with stage II N0 disease, associated with abdominal RTH. In patients with anaplastic WT that was staged higher than I or with a clear-cell sarcoma of the kidney, trends that indicate the efficacy of anthracyclines and alkylating agents^11,12 have led to the design and evaluation of a four-drug treatment schedule of AVE and ifosfamide (DEVI) together with abdominal RTH in stages II and III tumors. This study presents the results of the SIOP 9 trial and the results that concern patients initially assigned to the preoperative chemotherapy schedule.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1: APPENDIX 2: REFERENCES

 
Patients
One hundred nineteen European centers participated in the study (Appendix 1). Fifty-seven were already involved in the previous SIOP studies and routinely used preoperative chemotherapy. The 62 other centers, which belong to the German Pediatric Oncology and Hematology Society (GPOH) and where surgery was previously recommended as initial treatment, joined the study 13 months after its initiation. Centers that participated in the trial were expected to enter all renal tumor cases referred to them in one of the following two categories: study at registration or pre-eligible for the trial.

Study patients at registration. Exclusion criteria were as follows: age > 16 years or < 6 months, dubious clinical diagnosis of WT, registration after nephrectomy, presentation with bilateral or stage IV disease, and inability to receive the chemotherapy or comply with the follow-up schedule for social or medical reasons.

Pre-eligible patients. Children had to be older than 6 months or younger than 16 years at the time of the diagnosis of a unilateral renal tumor presenting clinical and radiologic characteristics of a nephroblastoma, have no detectable distant metastases, and be referred before receiving any previous treatment for their tumor. They received 4 weeks of chemotherapy as initial treatment. Thereafter, pre-eligible patients were classified as eligible or ineligible for the trial, and only the former were randomized.

Eligible patients. Entry onto the trial was restricted to patients who responded to the first 4 weeks of chemotherapy, given according to the protocol, and in whom tolerance did not contra-indicate 4 further weeks of the same treatment. Response was evaluated by comparing physical examination findings, tumor dimensions, and structural changes (ultrasound or computed tomography scan). Eligible patients also had to be free of metastases at the time of randomization. For the GPOH centers, the parents’ informed consent was mandatory before randomization and inclusion of the patients in the trial; this was not required by the ethical laws of the other participating countries at the time of the initiation of this study. Ineligible patients (not randomized) were operated on after the initial 4 weeks of chemotherapy and then entered onto the study.

After completion of the preoperative treatment and surgery, patients were assigned to different postoperative treatment groups according to tumor stage and histologic subtype, as reported by the institutional pathologist. However, it was recommended that a review be requested of the reference pathologist in case of doubtful classification and especially for stage I tumors with a favorable histology; any patients with changes signaled were reconsidered for therapy. SIOP staging and the histologic classification are given in Tables 1 and 2. Treatment groups are defined in Fig 1. All registered patients, independent of their trial or study status, were included in the follow-up.

View larger version (15K): [in this window] [in a new window]   Fig 1. SIOP 9 protocol (stages I to III).

A baseline value of 53% was used for the proportion of stage I cases to calculate the number of patients required. This estimated proportion was the weighted mean of the proportion previously observed in SIOP 5, arm C (43%), and in SIOP 6 (56%). Because we then decided that a power of 80% would be required to ensure a 15% increase in the frequency of stage I (when 8 weeks of preoperative treatment were given instead of 4 weeks), we had to include approximately 150 patients per group.¹⁴ No comparative study was designed for postoperative treatments. However, because no postoperative RTH was given in patients with stage II N0 disease, and to detect an unacceptable abdominal recurrence rate as soon as possible within the first year after surgery, a sequential survey rule was designed¹⁵ to evaluate the 1-year abdominal recurrence rate. A stratified log-rank test¹³ and a specific competing risks method^16,17 were used to compare survival distributions. Data were recorded and analyzed using a general database management system: Programme Interactif de Gestion et d’Analyse Statistique.¹⁸

Therapy Protocols
Regarding preoperative chemotherapy, all pre-eligible patients were to receive the same 4-week treatment that consisted of VCR and AMD injections. Patients assigned to the 8-week protocol received another 4-week cycle of the same drugs. The doses, frequency, and timing of treatment administered are shown in Fig 2. The initial protocol design established that AMD was to be given in a single dose calculated according to the body-surface area. Unexpected severe hepato-toxicity caused concern that the mode of administration and dosage of AMD might be more toxic than was expected based on the previous SIOP and other published experiences.^19-21 The SIOP Committee amended its protocol in April 1989 and changed the single injection of AMD at a dose of 0.45 mg/m²/body-surface area to the classic 3- or 5-day fractionated doses of 15 µg/kg of body weight. At the same time, a dose reduced to two thirds of the original dose, administered to patients younger than 1 year, was extended to those with a body weight of less than 12 kg.

View larger version (28K): [in this window] [in a new window]   Fig 2. SIOP 9 treatment schedules.

Postoperative chemotherapy was started 1 week after surgery. Treatment groups were as follows (Fig 1): no further treatment in stage I disease with a favorable histology; AV in stage I disease with a standard histology or anaplasia; AVE in stages II to III disease with a favorable or a standard histology, with or without RTH; DEVI in stages II to III anaplastic and stages I to III clear-cell sarcoma. Drugs, doses, and the frequency and timing of the different regimens are given in Fig 2. Postoperative treatment differed between the GPOH group and the others with respect to the use of anthracyclines. Doxorubicin was given in the GPOH group as in their previous studies, whereas in the other SIOP centers, epirubicin was given in the hope of limiting cardiac side effects. The dosage and timing of doxorubicin and epirubicin were the same in both regimens. Concerning AMD, the same changes in dosage described for preoperative treatment were applied for postoperative therapy.

Radiation therapy was indicated for stages II N1 and III tumors and also in stage II N0 tumors in the case of an unfavorable histology. The total dose that was to be delivered to the midplane was 15 Gy. A boost dose of 10 to 15 Gy was permitted for areas of residual disease or in the case of positive lymph nodes. The standard dose delivered for disease with an unfavorable histology was 30 Gy, in which case the boost was limited to 5 to 10 Gy.

Quality Control
The different speciality committees (Appendix 2) undertook a quality control review, which entailed the recording of the following information on clinical data and treatment: chemotherapy, radiation therapy, surgery and histopathology, along with the written surgical and pathologic reports and the simulation film for patients who received RTH. A review of the histologic specimens was mandatory for all of the patients registered.

Two centers, which together referred 12 patients, were excluded because of incomplete data, mainly concerning histologic records, specimens, and the follow-up of trial patients.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1: APPENDIX 2: REFERENCES

 
Trial
Tumor size and tumor clinical response to preoperative therapy. The initial volume of the tumor, ascertained by three-dimensional measurement on ultrasound studies performed at diagnosis, was available in 86% of the trial patients. The mean value observed was 470 mm³ (SD, 370 mm³). More than one half of the tumor volume had shrunk after 4 weeks of preoperative chemotherapy in 52% of the 267 assessable cases ( Table 5). The initial tumor size was not significantly different between the two arms, nor was the extent of tumor regression evaluated at the end of the initial 4-week chemotherapy course. After another 4 weeks, further tumor shrinkage of more than one half the volume was observed in 33% of the assessable cases, in patients treated according to the 8-week regimen.

View larger version (24K): [in this window] [in a new window]   Fig 3. EFS and OS according to preoperative randomized treatments.

Tumor volume regression. Tumor volume regression after 4 weeks of AV therapy was evaluated in 348 patients (Table 5). As expected, regression was significantly (P = .009) greater in trial patients than in nonrandomized patients. No correlation was found between tumor volume regression and stage after 4 weeks of chemotherapy (Table 5). When tumor histologic types were considered, regression at 4 weeks was poorer, as expected (P = .005), in the case of an unfavorable histology or non-Wilms’ tumors than among the favorable and standard histologic types of WT for which VCR and AMD are known to be efficient.

Tumor volume regression, evaluated at 4 weeks as greater than or less than 50% of the initial volume, was not significantly (log-rank test) related to either EFS (88% v 82% at 2 years) or OS (93% v 89% at 5 years). These nonsignificant results remained unchanged when the tumor volume regression considered was greater or less than 75%.

Stage distribution. The institutional tumor stage distribution for the entire pre-eligible population is listed in Table 6. The 56% rate of stage I tumors observed in the nonrandomized population is not significantly different from that of the trial patients (63%). Indeed, a 61% rate was obtained for the whole pre-eligible population.

Tumor rupture. Intraoperative tumor ruptures occurred in only 13 patients (2.6%). Spillage was reported in two cases and a simple fissure in 11 patients. Whole abdominal RTH was delivered to five patients who did not develop abdominal recurrences subsequently and were all alive at the time of this writing. Seven patients with a simple fissure received RTH to the tumor bed alone, based on the information given by the surgeons. Three of them developed a local recurrence (one 3 years later) and died. The quality control assessment found no anomalies in the RTH delivered. A last patient was initially erroneously staged and therefore received no RTH. He developed a local recurrence and died.

Non-Wilms’ tumors. Of the 28 non–clear-cell sarcomas or other non-Wilms’ tumors diagnosed by the institutional pathologist, five were considered as WT by the review panel. Two other tumors considered as WT according to the institutional diagnosis were diagnosed as non-Wilms’ tumor once reviewed by the panel. Twenty-eight (5.5%) received inappropriate preoperative treatment. Eight (1.6%) presented with a benign tumor or no tumor: mesoblastic nephroma (n = 3), cystic nephroma (n = 2), pyelonephritis (n = 1), hydronephrosis (n = 1), and a pseudotumor (n = 1). Two of the eight were randomized to receive the 8-week schedule, one was randomized to receive the 4-week schedule, and the other five were not randomized and received only the initial 4-week schedule. None of them exhibited signs of chemotherapy-related toxicity, and all were alive at the time of this writing. The 20 other non-WTs were malignant: nine neuroblastomas, two non-Hodgkin’s lymphomas, five malignant rhabdoid tumors of the kidney, and four carcinomas. Death was a result of disease in two patients with neuroblastoma, one with a lymphoma, and two with a malignant rhabdoid tumor of the kidney. The remaining 15 were all doing well at the time of this writing, with a follow-up of more than 3 years in all cases. One patient, who suffered from neuroblastoma and who was still alive at the time of this report, presented with transient hepatic toxicity.

At diagnosis, of the 62 fine-needle biopsies performed on the 852 registered patients, only three concerned the 28 patients reported here, and this technique failed to diagnose two neuroblastomas and one malignant rhabdoid tumor. Among the 28 patients, fine-needle biopsy was not performed in any of the 12 who were older than 5 years.

Tolerance of preoperative treatment. Toxicity related to preoperative chemotherapy was the reason for dose or timing changes in 11% (27 of 511) of the pre-eligible population. Toxicities reported were as follows: hepatic in 27, thrombocytopenia in 22, leukopenia in 20, anemia in 12, digestive in 17, and neurologic in six. Fifteen of these patients had veno-occlusive disease of the liver, as reported in another article.¹⁷ One patient died of infection, leukopenia, and thrombocytopenia associated with hepatic toxicity before the nephrectomy. Toxicity during preoperative treatment was the reason for not administering any postoperative treatment in one patient who had veno-occlusive disease and for definitively omitting VCR in another patient who had severe neurologic toxicity. Preoperative treatment-related toxicity and the ensuing changes were not significantly associated with a delay in the timing of surgery, stage distribution, or the outcome of the patients.

Histologic review. The panel of pathologists reviewed the histologic slides of 95% (487 of 511) of the pre-eligible patients. The findings of the review panel are listed in Table 8. The institutional diagnosis was confirmed by the review panel in 82% of the cases. Fewer tumors of standard histology (14%; 52 of 372) and of a favorable histology (27%; 3 of 11) were misclassified than tumors of an unfavorable histology: 36% (eight of 22) for anaplasia and 50% (eight of 16) for clear-cell sarcoma.

Results according to the postoperative treatment administered are shown in Figs 4 and 5. Two-year EFS and 5-year OS rates were as follows: for patients who received no postoperative treatment (stage I, favorable histology), 100% and 100%; for AV recipients (stage I, standard and anaplastic), 86% and 93%; for AVE recipients (stage II N0 standard), 82% and 87%; for patients who received AVE RTH (stages IIN1 and III), 77% and 89%; and for DEVI recipients (unfavorable histology), 64% and 79%, respectively. Abdominal recurrences occurred in 6.6% (five of 75) of patients with a stage II N0 tumor treated according to the AVE protocol without RTH.

View larger version (29K): [in this window] [in a new window]   Fig 4. EFS according to postoperative treatment groups.

View larger version (30K): [in this window] [in a new window]   Fig 5. OS according to postoperative treatment groups.

View larger version (27K): [in this window] [in a new window]   Fig 6. EFS according to histologic subtypes.

View larger version (27K): [in this window] [in a new window]   Fig 7. OS according to histologic subtypes.

View larger version (20K): [in this window] [in a new window]   Fig 8. EFS according to study status.

View larger version (21K): [in this window] [in a new window]   Fig 9. OS according to study status.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1: APPENDIX 2: REFERENCES

In previous SIOP studies, preoperative treatment proved efficient in reducing the tumor volume² and significantly lowering the number of tumor ruptures.¹ Surgical complications other than ruptures were, moreover, less frequent than those reported in the NWTS studies in which surgery was the primary treatment.^23,24 The overriding advantage of this approach is the downstaging of tumors to stage I disease, which is easily cured with a short, nonaggressive chemotherapy regimen. The central question in this study was whether prolonged preoperative therapy could significantly increase the number of patients with stage I disease. The longer schedule conferred no advantage because a similar percentage of stage I tumors were observed in each arm. The final overall proportion of stage I tumors among the 382 trial patients was approximately 63%, as opposed to the 53% expected, based on previous studies. Although the baseline value used to calculate the required number of subjects was inaccurate, the power of the study was maintained. The improvement observed cannot therefore be attributed to the longer treatment. It is noteworthy that if this study had not been conducted according to a randomized design but using a historical control group, the conclusion would have been erroneously in favor of the longer preoperative treatment. Taking into account all of the pre-eligible population, the 61% rate of stage I tumors remains higher than expected and also higher than in any other published series. Results observed in terms of EFS and OS in the stage I group were comparable to those published for patients with stage I disease who underwent primary surgery.^7,22 Given the high rate of stage III tumors and the low rate of stage I disease observed in their first study, the United Kingdom Children’s Cancer Study Group is still addressing the question of which initial management strategy is best in patients with WT.²² In an attempt to obtain definitive answers, there is a head-on-head randomized comparison in the on-going United Kingdom Children’s Cancer Study Group 3 study of immediate surgery versus 6 weeks of preoperative VCR and AMD in children older than 6 months with nonmetastatic unilateral WT.

There are also disadvantages to prolonging preoperative therapy. Patients incorrectly diagnosed at admission will receive more chemotherapy if the diagnosis is made after 8 weeks instead of 4. However, in this study, only 1.6% of the patients were treated for a benign condition and received the recommended chemotherapy, which is 0.008% of the entire population of registered patients. This is consistent with the previous findings in SIOP studies. Toxicity resulting from preoperative chemotherapy was not significantly different between the two arms. The long-duration schedule, however, implies more frequent visits to the hospital and a substantially heavier financial burden. A single intensive dose of AMD when decreased to 45 µg/kg/dose was shown to be as effective as and less toxic than the 5-day regimen with the same drug in the NWTS 4 study and is another way to reduce the cost of therapy.⁷ In the same study, it was also shown that recurrence-free survival and OS rates were not worse among the patients who received a short 6-month course of postoperative chemotherapy compared with those who received treatment lasting 9 additional months according to the classic schedule, and this was true both for fractionated doses of AMD over 5 days and for a single dose of the same drug.²⁵ In the on-going SIOP93-01 study, two postoperative treatment schedules, 4 weeks versus the classic 18-week schedule, are being compared in a randomized trial for stage I WT with an intermediate risk or with anaplasia.

A further goal of the NWTS and SIOP studies is to continue limiting RTH without increasing the risk of local or abdominal recurrences.²⁶ In the SIOP 9 study, RTH was limited to stages IIN1 and III tumors of favorable or standard histology and to stages greater than I for tumors of an unfavorable histology. When indicated, radiation doses were reduced in comparison with those given in the SIOP 6 study. RTH was therefore indicated in only 21% of the patients in SIOP 9. The 6% rate of abdominal or local recurrences observed as first events in the entire population treated preoperatively and postoperatively according to the recommended regimens is acceptable compared with the 8% observed in SIOP 6. However, among the 41% (190 of 461) of the patients assigned a regimen including an anthracycline, de-escalation of RTH in patients with stage II N0 disease was the reason in one half of them. The risks and benefits of this approach in terms of long-term sequels have yet to be evaluated.

The current strategy for the treatment of patients presenting with a WT is based on the identification of different risk groups according to histopathologic features. The role of the pathologist is preponderant, and an early review of cases by an expert is recommended in multicenter studies.

In conclusion, the 4-week schedule of pre-nephrectomy chemotherapy should henceforth be considered the standard treatment. Clinical trials should continue to improve the cure rate of high-risk patients and the quality of life of those with a more favorable prognosis by tapering therapy to the minimum required. In this context of tailoring treatment to risk groups of patients identified on the basis of tumor stage and histologic type, the role of the pathologist is of paramount import.

	APPENDIX 1:

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1: APPENDIX 2: REFERENCES

 
SIOP 9 Nephroblastoma Trial and Study—Participating Centers

	APPENDIX 2:

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1: APPENDIX 2: REFERENCES

	ACKNOWLEDGMENTS

We thank the pediatricians, surgeons, pathologists and radiation therapists who treated these children in the different participating centers. We also thank the computer scientists, statisticians, and data managers for the quality of their work in the management of the data and of the computerized files. We are grateful to Lorna Saint-Ange for editing the article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1: APPENDIX 2: REFERENCES

 
1. Lemerle J, Voûte PA, Tournade MF, et al: Pre-operative versus post-operative radiotherapy, single versus multiple courses of actinomycin D in the treatment of Wilms’ tumor. Preliminary results of a controlled clinical trial conducted by the International Society of Paediatric Oncology (SIOP). Cancer 38: 647-654, 1976[Medline]

2. Lemerle J, Voûte PA, Tournade MF, et al: Effectiveness of pre-operative chemotherapy in Wilms’ tumor: Results of an International Society of Pediatric Oncology (SIOP) clinical trial. J Clin Oncol 1: 604-609, 1983[Abstract]

3. Tournade MF, Com-Nougué C, Voûte PA, et al: Results of the Sixth International Society of Pediatric Oncology Wilms’ Tumor Trial and Study: A risk-adapted therapeutic approach in Wilms’ tumor. J Clin Oncol 11: 1014-1023, 1993[Abstract/Free Full Text]

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6. D’Angio JG, Breslow N, Beckwith JB, et al: The treatment of Wilms’ tumor: Results of the Third National Wilms’ Tumor Study. Cancer 64: 466-479, 1989[Medline]

7. Green D, Breslow N, Beckwith JB, et al: Comparison between single-dose and divided dose administration of dactinomycin and doxorubicin for patients with Wilms’tumor: A report from the National Wilms’ Tumor Study Group. J Clin Oncol 16: 237-245, 1998[Abstract/Free Full Text]

9. Breslow N, Churchill G, Beckwith JB, et al: Prognosis for Wilms’ tumor patients with nonmetastatic disease at diagnosis: Results of the Second National Wilms’ Tumor Study. J Clin Oncol 3: 521-531, 1985[Abstract]

8. Jereb B, Tournade MF, Lemerle J, et al: Lymph node invasion and prognosis in nephroblastoma. Cancer 45: 1632-1635, 1980[Medline]

10. Com-Nougué C, Rey A, Ducourtieux M, et al: Some problems which arise when testing the equivalence of two survival distributions. Rev Epidemiol Sante Publique 43: 84-95, 1995[Medline]

11. Green DM, Beckwith JB, Breslow NE, et al: The treatment of children with stages II-IV anaplastic Wilms’ tumor: A report from the National Wilms’ Tumor Study Group. J Clin Oncol 12: 2126-2131, 1994[Abstract/Free Full Text]

12. Tournade MF, Lemerle J, Brunat-Mentiny M, et al: Ifosfamide is an active drug in Wilms’ tumor: A phase II study conducted by the French Society of Pediatric Oncology. J Clin Oncol 6: 793-801, 1988[Abstract/Free Full Text]

13. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 35: 1-39, 1977[Medline]

14. Casagrande JT, Pike MC, Smith PG, et al: An approximate formula for calculating sample size for comparing two binomial distributions. Biometrics 34: 483-486, 1978[Medline]

15. Armitage P: Sequential Medical Trials. Oxford, United Kingdom, Blackwell Scientific, 1960

16. Marubini E, Vaisecchi MG: Competing Risks. Analyzing Survival Data From Clinical Trials and Observational Studies. New York, NY, John Wiley & Sons, 1995

17. Com-Nougué C, Guérin S, Rey A: Estimation des risques associés à des événements multiples. Rev Epidemiol Sante Publique 47: 75-85, 1999[Medline]

18. Wartelle M, Kramar A, Jan P, et al: PIGAS: An interactive statistical database management system, in Hammond R, Mac Carty JL (eds): Proceedings of the Second International Workshop on Statistical Database Management, Los Altos, California, Sept 27-29, 1983. Laurence Berkeley Laboratory Statistics Canada, pp 124-132

19. Bisogno G, de Kraker J, Weirich A, et al: Veno-occlusive disease of the liver in children treated for Wilms’ tumor. Med Pediatr Oncol 29: 245-251, 1997[Medline]

20. Ludwig R, Weirich A, Ulrich A, et al: Hepatotoxicity in patients treated according to the Nephroblastoma Trial and Study SIOP9/GPOH. Med Pediatr Oncol 33: 462-469, 1999[Medline]

21. Green A, Norkool P, Breslow NE, et al: Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: A report from the National Wilms’ Tumor Study. J Clin Oncol l8: 1525-1530, 1990[Abstract]

22. Pritchard J, Imeson J, Barnes J, et al: Results of the United Kingdom Children’s Cancer Study Group First Wilms’Tumor Study. J Clin Oncol 13: 124-133, 1995[Abstract/Free Full Text]

23. Godzinski J, Tournade MF, de Kraker J, et al: Rarity of surgical complications after postchemotherapy nephrectomy for nephroblastoma. Experience of the International Society of Paediatric Oncology Trial and Study "SIOP-9". Eur J Pediatr Surg 7: 1-4, 1997

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Submitted October 13, 1999; accepted September 11, 2000.

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