Randomized Trial of Prophylactic Granulocyte Colony-Stimulating Factor During Rapid COJEC Induction in Pediatric Patients With High-Risk Neuroblastoma: The European HR-NBL1/SIOPEN Study

  1. Andrew Pearson
  1. From St. Anna Children's Hospital; Children's Cancer Research Institute; Austrian Institute of Technology, Vienna, Austria; Institut Gustave Roussy, Villejuif, France; Great Ormond Street Hospital, London; The Children's Cancer and Leukaemia Group, University of Leicester, Leicester; Royal Marsden Hospital, Sutton, United Kingdom; Schneider Children's Medical Center of Israel, Petah Tikva, Israel; Hospital Universitario Infantil La Fe, Valencia, Spain; Ghent University Hospital, Ghent, Belgium; University Hospital Motol, Prague, Czech Republic; Athens General Paediatric Hospital, Athens, Greece; Portuguese Institute of Oncology, Lisbon, Portugal; Rikshospitalet, Oslo, Norway; Astrid Lindgren Children's Hospital, Karolinska Hospital, Stockholm, Sweden; Semmelweiß University, Budapest, Hungary; Jagiellonian University Medical College, Kraków, Poland; University Hospital of Aarhus, Aarhus, Denmark; University Hospital, Lausanne, Switzerland.
  1. Corresponding author: Ruth Ladenstein, MD, MBA, St. Anna Children's Hospital, Kinderspitalgasse 6, Vienna, Austria 1090; e-mail: ruth.ladenstein{at}ccri.at.

  1. U.P. and A.P. have contributed equally to this article and share senior authorship.

 
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Abstract

Purpose To reduce the incidence of febrile neutropenia during rapid COJEC (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide given in a rapid delivery schedule) induction. In the High-Risk Neuroblastoma-1 (HR-NBL1) trial, the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) randomly assigned patients to primary prophylactic (PP) versus symptom-triggered granulocyte colony-stimulating factor (GCSF; filgrastim).

Patients and Methods From May 2002 to November 2005, 239 patients in 16 countries were randomly assigned to receive or not receive PPGCSF. There were 144 boys with a median age of 3.1 years (range, 1 to 17 years) of whom 217 had International Neuroblastoma Staging System (INSS) stage 4 and 22 had stage 2 or 3 MYCN-amplified disease. The prophylactic arm received a single daily dose of 5 μg/kg GCSF, starting after each of the eight COJEC chemotherapy cycles and stopping 24 hours before the next cycle. Chemotherapy was administered every 10 days regardless of hematologic recovery, provided that infection was controlled.

Results The PPGCSF arm had significantly fewer febrile neutropenic episodes (P = .002), days with fever (P = .004), hospital days (P = .017), and antibiotic days (P = .001). Reported Common Toxicity Criteria (CTC) graded toxicity was also significantly reduced: infections per cycle (P = .002), fever (P < .001), severe leucopenia (P < .001), neutropenia (P < .001), mucositis (P = .002), nausea/vomiting (P = .045), and constipation (P = .008). Severe weight loss was reduced significantly by 50% (P = .013). Protocol compliance with the rapid induction schedule was also significantly better in the PPGCSF arm shown by shorter time to completion (P = .005). PPGCSF did not adversely affect response rates or success of peripheral-blood stem-cell harvest.

Conclusion Following these results, PPG-GSF was advised for all patients on rapid COJEC induction.

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INTRODUCTION

Neuroblastoma (NBL), the most common extracranial solid tumor of childhood, remains associated with an unfavorable prognosis in the presence of high-risk features such as metastases in patients older than age 12 to 18 months,1 amplification of the MYCN oncogene,2–5 and unfavorable histology.6

Recent progress appears to be related to chemotherapy dose intensity7 and improved supportive care. In particular, a significant dose response is seen with cisplatin and cyclophosphamide.8–10 To date, there have been two randomized studies on induction intensity11,12 and three randomized studies showing the advantage of myeloablative therapy as consolidation therapy.13–15

The European Neuroblastoma Study Group-5 (ENSG5) study12 has demonstrated a significant benefit in event-free survival and overall survival for the rapid schedule COJEC (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide given in a the rapid delivery schedule), which achieved a 1.8-fold increase in dose intensity over conventional induction OPEC/OJEC (vincristine, cisplatin, etoposide, cyclophosphamide/vincristine, carboplatin, etoposide, cyclophosphamide) 16 but caused profound myeloaplasia over 70 days.

The genetically engineered growth factor, recombinant human granulocyte colony-stimulating factor (r-metHuGCSF, filgrastim) stimulates production and maturation of neutrophils in vivo.17 Clinical studies in children suggest that primary prophylactic GCSF (PPGCSF) reduces the incidence of febrile neutropenia and confirmed infections in patients receiving high-intensity, dose-intensive chemotherapy for high-risk, advanced-stage tumors.18–22 Of the studies assessing PPGCSF in childhood cancer, most did not show a reduction in febrile neutropenia rate. Trials either lacked power to demonstrate an effect or were not randomized with comparable cohorts of patients.19,23–28

To the best of our knowledge, this is the first report of the results of randomized use of PPGCSF in a rapid dosing schedule for high-risk NBL aiming to decrease the incidence of febrile neutropenia and associated risks during the induction phase.

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PATIENTS AND METHODS

Patients

The ongoing High-Risk Neuroblastoma-1 trial by the International Society of Paediatric Oncology European Neuroblastoma Group (HR-NBL1/SIOPEN) recruited 430 patients in 111 European centers from May 2002 to November 2005. Eligible patients were age 1 to 21 years and had stage 4 or MYCN-amplified stage 2 or 3 NBL (Table 1). Participation in the PPGCSF randomization was optional but 239 patients, 145 of whom were boys, from 74 centers were randomly assigned: 119 to PPGCSF and 120 to the control arm with symptom-triggered GCSF (STGCSF) only giving a randomization rate of 55% (Fig 1). The median age at diagnosis of randomly assigned patients was 3.0 years (range, 1 to 17 years); 217 patients had stage 4 disease, and 22 patients had stage 2 or 3 MYCN-amplified disease. Patient characteristics are presented in Table 2. The PPGCSF and STGCSF groups were similar in age, sex, stage, and primary and metastatic sites. Metastatic disease at diagnosis was seen in 217 of 239 randomly assigned patients.

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Table 1.

Overall Recruitment and Randomization Rates per Country

Fig 1.
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Fig 1.

Flow chart of progress of patients through the trial showing interventional use of granulocyte colony-stimulating factor (GCSF+; filgrastim) in the control group per cycle. pt, patient; T, toxicity; P, progression; R, poor response; D, parental decision.

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Table 2.

Patient Characteristics at Diagnosis

Eligibility for the HR-NBL1/SIOPEN Trial

Diagnosis of high-risk NBL followed the International Neuroblastoma Staging System (INSS).29 Written informed consent for random assignment was obtained for all patients. Data were collected on the Web-based SIOPEN Research Network (SIOPEN-R-NET) remote data entry (RDE) database (https://www.siopen-r-net.org/) designed for the HR-NBL1/SIOPEN study. Ethical and regulatory authority approval was obtained according to the European Directive in each country. Adverse events were monitored in real time using the RDE system.

Trial Design

This report focuses on the induction phase, which consisted of eight courses of alternating cycles (A, B, and C) every 10 days. The schedule is depicted in Figure 2. In children weighing < 12 kg, drug doses were calculated per kilogram, not by body surface area (square meters).

Fig 2.
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Fig 2.

Treatment scheme of the High-Risk Neuroblastoma-1 International Society of Paediatric Oncology European Neuroblastoma Group (HR-NBL1/SIOPEN) trial induction phase. Rapid COJEC, cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide given in a rapid delivery schedule; CBDCA, carboplatin 750 mg/m2 short infusion; VP16, etoposide 175 mg/m2 as 4-hour infusion; VCR, vincristine 1.5 mg/m2 intravenous bolus; CDDP ctn., cisplatin 80 mg/m2 as a 24-hour continuous infusion; CYC, cyclophosphamide 1,050 mg/m2 short infusion. A, B, and C are rapid COJEC courses; (▾) GCSF at 5 μg/kg/d between COJEC courses. (*) indicates prolonged or higher dose of granulocyte colony-stimulating factor (GCSF) to stimulate peripheral blood stem cells (PBSC) for harvest; (★) staging using magnetic resonance imaging, computed tomography, ultrasound, iodine 123-meta-iodobenzylguanidine scan, and bone marrow (BM) aspirates and biopsies; (☆) staging using BM aspirates only and local US; ([circled R]) Random assignment for primary prophylactic GCSF versus symptom-triggered GCSF. HR-NBL1/SIOPEN randomized trial basic treatment concept: in case of adequate response per trial guidelines, induction is followed by PBSC harvest, aimed surgical resection of the primary tumor, myeloablative therapy, radiation to the primary site, and minimal residual disease treatment.

Objectives of the PPGCSF Randomization

The primary aim was to see whether GCSF could reduce the incidence of febrile neutropenic episodes during rapid COJEC. The results of randomization were expected early on and it was assumed that PPGCSF would become standard therapy for the rest of the study if the primary end point was met and no adverse effects on peripheral-blood stem-cell harvest (PBSCH) were observed.

Mode of Administration of PPGCSF

Patients randomly assigned to the PPGCSF arm were given a single daily subcutaneous or intravenous injection of filgrastim 5 μg/kg/d between COJEC courses, starting 24 hours after and stopping 24 hours before chemotherapy. Filgrastim was discontinued if the absolute neutrophil count was ≥ 10 × 109/L. All patients received GCSF after the last course (cycle B) up to completion of PBSCH (Fig 2).

Mode of Administration of STGCSF

Treating physicians were encouraged to use therapeutic GCSF in the control arm for severe or life-threatening infections30–32 together with antibiotics and antifungal therapy in children at particular risk (ie, proven Pseudomonas or fungal infections, multiorgan dysfunction, or pneumonia). Secondary prophylaxis with GCSF (ie, administration after one febrile neutropenic episode in subsequent cycles) was not recommended.

Laboratory and Physical Measurements

Patients who developed febrile neutropenia (absolute neutrophil count < 0.5 × 109/L and axillary temperature > 38.0°C) were to be hospitalized. Following an infection screen, empirical parenteral antibiotic therapy was to be immediately initiated according to local hospital standards. Axillary temperature, concomitant drug administration, and blood product requirements were recorded on the RDE system. Physical examination, vital signs, and weight were recorded weekly. CBCs and liver and kidney function were checked before each course.

Supportive Care During Induction

Supportive care guidelines were extensive. The use of central lines was strongly recommended. Antiemetic therapy was administered according to institutional guidelines. Clear instructions were given concerning nutritional support, hydration, Pneumocystis carinii pneumonitis prophylaxis, blood product support, kidney function monitoring, and treatment of febrile neutropenia. An aggressive and early interventional approach was adopted toward potential fungal infection.

PBSCH

Tumor response was assessed after four and eight courses of rapid COJEC. Patients with disease progression at any time or an inadequate metastatic response after completion of COJEC went off study to receive alternative therapy. After full restaging, patients achieving a complete response or partial response at metastatic sites, based on iodine-123-meta-iodobenzylguanidine scan (123I-mIBG) scanning and cytomorphologic evaluation of two bone marrow aspirates, were eligible for PBSCH. Alternative harvest options were steady-state mobilization before or after surgery and, if required, additional bone marrow harvest.

Randomization and Statistical Methods

Randomization, on an intent-to-treat basis, was by minimization33 before day 2 of COJEC. Two-sided significance tests were used throughout (alpha = 5%).

Sample Size

The expected average number of 0.5 febrile episodes per course (four in eight courses) was estimated from the ENSG5 study, in which COJEC without GCSF prophylaxis was given. We aimed to show an average reduction of one febrile episode in eight courses or a mean reduction of febrile episodes of 0.365 per course in the PPGCSF arm. The anticipated standard deviation was 0.3. To achieve a power of 80% with a type I error rate of 5% required a total sample size of 184 patients. To control for a potential misspecification of the standard deviation, an interim analysis was planned after 92 patients to allow for a re-estimation of the final sample size.34

Primary End Point

The primary end point was reduction of febrile neutropenia during COJEC. The difference in the number of febrile episodes per course was primarily analyzed, following the pre-established analysis plan, using the modification of the two-sample t test described by Denne et al.34

Secondary End Points

Secondary end points included hospitalization days, documented infection rate, parenteral antibiotics days, number of packed RBC/platelet transfusions, chemotherapy delay, infection-related mortality, and signs of stem-cell pool depletion using harvest days and numbers of CD34+ cells. In addition, times to completion of COJEC, as a measure of chemotherapy dose intensity, and rate of remission at the end of induction and eligibility for myeloablative therapy (MAT) randomization were studied.

Not all patients completed COJEC induction. To adjust for the different number of administered cycles, the mean number of days in hospital per cycle (ie, total hospital days per number of given cycles) was used. The same approach was used for antibiotic and fever days. For the analysis of secondary end points, the χ2 test, Mantel-Haenszel log-rank test, and Wilcoxon rank sum test were used.35 In addition, a generalized linear mixed model for binary data was used for repeated measures (ie, toxicity data for multiple cycles/patients and equally to compare the proportion of febrile episodes of both arms).36

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RESULTS

Patients

A total of 110 patients in the PPGCSF arm and 114 in the control arm completed the study. All 239 randomly assigned patients were included in the efficacy and safety analysis on an intention-to-treat basis (Fig 1). Of these, 232 (97%) were evaluable for the primary end point.

Efficacy

Regarding the primary end point, the incidence of febrile episodes (> 38°C) was lower in the PPGCSF arm for each course. The mean number of febrile neutropenic episodes in the PPGCSF arm (117 evaluable patients of 119 patients) was 2.3 ± 2 (median, 2) over eight courses and 3.0 ± 2 (median, 3) in the control arm (115 evaluable patients of 120 patients). There was a significant overall median and mean reduction in febrile episodes by 1 and 0.6, respectively (P = .002; Fig 3). Regarding secondary end points, the significant benefits of PPGCSF during COJEC induction are summarized in Table 3 and include eight fewer hospital days, two fewer febrile days, and 7.5 fewer antibiotic days.

Fig 3.
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Fig 3.

Febrile episodes over eight rapid COJEC (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide given in a rapid delivery schedule) courses including Common Toxicity Criteria grades 2 to 4. GCSF+, granulocyte colony-stimulating factor administered; GCSF−, control group without primary prophlactic but interventional use as outlined in Figure 1.

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Table 3.

Summary of Results

Toxicities

The main Common Toxicity Criteria (CTC) grade 4 toxicity was hematologic: PPGCSF-arm, WBC aplasia and neutropenia 38% and 50%, respectively, and STGCSF-arm, 57% and 70%, respectively (P < .001; Table 3). The overall transfusion rate per course was similar in both arms. The median number of packed RBC transfusions throughout induction was 6.5 for the PPGCSF arm and seven for the STGCSF arm. The incidence of severe thrombocytopenia (platelet count < 20 × 109/L) was similar, a median number of seven platelet transfusions being given in both arms.

Grade 4 CTC toxicities, other than hematologic, ranged from 1% to 4%, depending on the treatment course, with the exception of the first cycle where it was 11% (Fig 4). A favorable impact of PPGCSF was observed on gut toxicities grades 2 to 4 showing a significantly reduced incidence of mucositis, nausea/vomiting, and constipation. A lower frequency of severe weight loss of > 10% was observed in the PPGCSF arm. After course 8, weight loss was 11% in the PPGCSF arm and 25% in the STGCSF arm (P = .013).

Fig 4.
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Fig 4.

Overview on grade 4 toxicities during rapid COJEC (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide given in a rapid delivery schedule) induction according to randomized arm. GCSF+, granulocyte colony-stimulating factor administered; GCSF−, GCSF not administered. (*) All Common Toxicity Criteria (CTC) scores; (†) CTC scores excluding hematologic (hema) toxicities.

Protocol Compliance, Safety, and On-Study Events

In the control arm, 106 (88%) of 120 patients had complete data of whom 53 (50%) received filgrastim for febrile neutropenia and/or severe infections. The incidence of STGCSF increased over time and was 5% and 11% (6 and 12 patients) for the two A courses, 4%, 8%, 11%, and 37% (5, 9, 12, and 37 patients) for the four B courses, and 9% and 21% (10 and 23 patients) for the two C courses.

Withdrawal of Patients During Rapid COJEC

In the PPGCSF arm, five patients were withdrawn: one after course 5 (for persistent prolonged thrombocytopenia with enteropathy, ascites, and melena) and four after course 7 (two for poor response/progression and two for renal toxicity; Fig 2).

In the STGCSF arm, six patients were withdrawn: two after courses 4 and 5 for poor response/tumor progression, one after course 5 after parental decision, and three after course 7 (one with renal toxicity and two with infectious complications: one Fusarium and one Enterobacter cloacae).

Tolerance and Chemotherapy Dose Reductions

Tolerance to filgrastim was good, with only expected adverse effects reported. Documented chemotherapy dose reductions, by up to one third, ranged from 3% to 7% throughout the eight COJEC courses (course A, 3%; B, 2% to 4%; and C, 5% to 7%). In the majority of patients (93% to 97%), depending on the respective courses (A, B, or C), no dose reduction was reported. Reductions within both arms are summarized in Appendix Table A1 (online only) and were not statistically different.

Severe Infections

Severe infections (CTC grade 4) were recorded for 18 patients, with no statistical difference between arms. Six had pneumonia and nine had septicemia, of whom five presented with septic shock. There were two severe urinary tract infections and one severe soft tissue infection.

Fungal Infections

Severe systemic fungal infection appeared less frequently in the PPGCSF arm and was not statistically significant. In the PPGCSF arm, 13 of 119 patients had fungal infection; five (4%) were severe (four pulmonary aspergillosis, one Candida septicemia). In the STGCSF arm, 17 of 120 patients had fungal infection; eight (7%) were severe (six pulmonary aspergillosis, one Candida septicemia, and one Fusarium).

Admittance to Intensive Care

Equivalent numbers of randomly assigned patients were admitted to intensive care: five on the PPGCSF arm and six on the STGCSF arm. In the PPGCSF arm, two patients were admitted early for biopsy or tumor-related problems, and three were admitted later because of treatment toxicity. In the STGCSF arm, one was admitted early for tumor-related problems, and five were admitted later for treatment toxicity.

Deaths on Study

A total of four deaths occurred, all in patients randomly assigned to the PPGCSF arm. One patient died of septicemia after delayed readmittance to the hospital, and three were early tumor-related deaths of whom two died of rapid tumor progression and one of bleeding post biopsy.

PPGCSF Effect on Study Milestones

The overall response rate for randomly assigned patients was 72%, with no difference between the two arms. There was no influence on the success rate of PBSCH. In the PPGCSF arm, 74 (91%) of 119 completed COJEC with a successful harvest, with 79 (89%) of 120 for the STGCSF arm. Equal percentages of patients went on to be randomly assigned for MAT.

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DISCUSSION

GCSF is a hematopoietic growth factor that decreases the duration and severity of neutropenia in adults and children receiving chemotherapy for cancer. Reduction in neutropenia is meaningful only if it is associated with improvement in clinical outcomes.37,38 The HR-NBL1/SIOPEN trial is, to the best of our knowledge, the first randomized study showing clinically relevant benefits of PPGCSF in children with newly diagnosed high-risk NBL receiving rapid COJEC induction. PPGCSF was also well tolerated.

Two French randomized pediatric trials investigated PPGCSF during NBL induction.8,26 Although both reported a reduction in duration of neutropenia and antibiotic use, neither observed a reduction in hospitalization or a decreased febrile neutropenia rate. These latter end points were both met in our study.

American Society of Clinical Oncology guidelines suggested applying adult recommendations to children.37,39,40 PPGCSF was recommended only when the expected incidence of febrile neutropenia was 40% or more.32,39,41,42 Our trial fulfilled these criteria because rapid COJEC, without the use of PPGCSF, had a febrile neutropenia rate of more than 50% in the ENSG5 study.12

Reduced febrile neutropenia and documented infection without an effect on infection-related mortality were described in the meta-analysis of Calderwood et al23 on PPGCSF in adults with either solid tumors or malignant lymphomas and that of Sung44 on randomized trials of PPGCSF in children with cancer. The latter found a 20% reduction in febrile neutropenia rate, a decreased length of hospital stay by approximately 2 days, and a 22% reduction in the documented infection rate but no association with a reduction in infection-related mortality. Our trial confirms these findings because there was no reduction in infectious mortality. Only one septic death was recorded in a patient with delayed admission to the hospital, and three early tumor-related deaths were recorded.

The above results are in line with the recommendations for PPGCSF in children in the Schaison et al study,21 implying its use in children following dose-intensive therapy for advanced-stage tumors such as NBL, soft tissue sarcoma, and osteosarcoma.

Even considering previous narrative reviews of PPGCSF in children with cancer,32,38,45,46 our study is important because it demonstrates the efficacy of PPGCSF in a rapid dosing schedule. Before this study was done, there was concern that the stem-cell pool might become exhausted by prolonged GCSF stimulation, resulting in insufficient numbers of peripheral-blood stem cells at harvest, preventing the children from proceeding to MAT/stem-cell reinfusion. We demonstrated that there was no adverse influence on the response rate or the PBSCH in the PPGCSF arm, and equal percentages of patients were randomly assigned to MAT. In addition, improved compliance to the schedule and shorter time to complete induction resulted in a better dose intensity in the PPGCSF arm. The overall compliance with the trial was excellent, with more than 95% of patients evaluable for final analysis.

Our study further demonstrated a number of additional clinically relevant advantages of PPGCSF: a lower rate and grade of fever and infection as well as fewer days in the hospital and fewer days on antibiotics (the main CTC grade 4 toxicity was hematologic). There was no influence on the overall transfusion rate/course which was similar in both arms for both RBC and platelet transfusions. There was no significant difference regarding fungal infections which, with strict treatment recommendations, decreased over time.

Although we did not use a specific quality-of-life (QoL) score, many outcome parameters reflecting QoL were significantly improved in the PPGCSF arm. As a measure of QoL, we were able to show that children had a significantly lower rate of severe weight loss (> 10%) and that there was a lower rate of gut toxicities, including mucositis, nausea/vomiting, and constipation. The latter is most likely related to less morphine-based analgesia. In addition, the child's general condition, graded according to CTC, showed a trend toward significance in this randomized setting. This is also supported by the American Society of Clinical Oncology guidelines presuming that the number of febrile neutropenic episodes, antibiotic therapy requirements, and need for hospitalization are indirect indicators of QoL.47

A cost calculation was not part of this study because of the 76 major hospitals in 16 countries involved, which would have resulted in a wide range of cost implications. However, a previous report27 on PPGCSF in children with non-Hodgkin's lymphoma treated with COPAD[M] (cyclophosphamide, vincristine, prednisone, doxorubicin, and high-dose methotrexate) intensive induction showed that the cost of 2 days of hospitalization was equivalent to the cost of 17 days of GCSF. In our study, the control arm spent, on average, 8 more days in the hospital and required 7.5 more days of antibiotics; 46% received STGCSF for severe infections. One could argue that the benefits of PPGCSF demonstrated in our study outweigh the cost.

Pediatric tumors with a high proliferation rate may be more effectively treated with dose-intensive chemotherapy plus prophylactic filgrastim. This trial contributes further to research on growth factors in the pediatric setting, underlining their importance and beneficial use in children as previously suggested in a European Organisation for Research and Treatment of Cancer (EORTC) study (Hann et al48).

The advantages of single-dose, long-lasting pegylated filgrastim over daily GCSF in children were previously demonstrated49–55 and are intriguing. However, if stimulating effects are not abrogated in a timely manner within a 10-day rapid schedule, pronounced severe aplasia or stem-cell pool depletion might occur if chemotherapy occurs early in cell cycle division.

In conclusion, our results support the recommendation of PPGCSF in the conventional intensive chemotherapy induction setting. We showed major clinical benefits from the use of PPGCSF during a rapid dosing schedule that reduce the high incidence of febrile neutropenia.

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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

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AUTHOR CONTRIBUTIONS

Conception and design: Ruth Ladenstein, Dominique Valteau-Couanet, Penelope Brock, Isaac Yaniv, Victoria Castel, Geneviève Laureys, Josef Malis, Vassilios Papadakis, Ana Lacerda, Ellen Ruud, Per Kogner, Miklos Garami, Walentyna Balwierz, Henrik Schroeder, Maja Beck-Popovic, David Machin, Andrew Pearson

Provision of study materials or patients: Ruth Ladenstein, Dominique Valteau-Couanet, Penelope Brock, Isaac Yaniv, Victoria Castel, Geneviève Laureys, Josef Malis, Vassilios Papadakis, Ana Lacerda, Ellen Ruud, Per Kogner, Miklos Garami, Walentyna Balwierz, Henrik Schroeder, Maja Beck-Popovic, Andrew Pearson

Collection and assembly of data: Ruth Ladenstein, Dominique Valteau-Couanet, Penelope Brock, Isaac Yaniv, Victoria Castel, Geneviève Laureys, Josef Malis, Vassilios Papadakis, Ana Lacerda, Ellen Ruud, Per Kogner, Miklos Garami, Walentyna Balwierz, Henrik Schroeder, Maja Beck-Popovic, Günter Schreier, Andrew Pearson

Data analysis and interpretation: Ruth Ladenstein, David Machin, Ulrike Pötschger

Manuscript writing: Ruth Ladenstein, Penelope Brock, Andrew Pearson

Final approval of manuscript: Ruth Ladenstein, Dominique Valteau-Couanet, Penelope Brock, Isaac Yaniv, Victoria Castel, Geneviève Laureys, Josef Malis, Vassilios Papadakis, Ana Lacerda, Ellen Ruud, Per Kogner, Miklos Garami, Walentyna Balwierz, Henrik Schroeder, Maja Beck-Popovic, Günter Schreier, David Machin, Ulrike Pötschger, Andrew Pearson

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Acknowledgment

We thank the parents and patients who participated in this study, the staff at hospital sites for patients' care, and Claudia Zeiner, MSc, for secretarial assistance.

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Appendix

⇓

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Table A1.

Summary of Dose Reductions

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Footnotes

  • Supported by EC Grants No. QLRI-CT-2002-01768 and C8346/A8177 from Cancer Research UK (United Kingdom), and from Amgen International and Amgen UK.

  • Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

  • Received November 26, 2009.
  • Accepted April 13, 2010.
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  1. Published online before print June 21, 2010, doi: 10.1200/JCO.2009.27.3524 JCO vol. 28 no. 21 3516-3524
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