Originally published as JCO Early Release 10.1200/JCO.2006.09.7527 on August 13 2007

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Phase III Trial of High-Dose Sequential Chemotherapy With Peripheral Blood Stem Cell Support Compared With Standard Dose Chemotherapy for First-Line Treatment of Advanced Ovarian Cancer: Intergroup Trial of the AGO-Ovar/AIO and EBMT

Volker Möbus, Hannes Wandt, Norbert Frickhofen, Carmelo Bengala, Kim Champion, Rainer Kimmig, Helmut Ostermann, Axel Hinke, Jonathan A. Ledermann

From the Department of Obstetrics and Gynecology, Städtisches Klinikum Frankfurt a.M.-Höchst; Department of Hematology and Oncology, Klinikum Nürnberg; Department of Hematology and Oncology, Dr Horst Schmidt Kliniken Wiesbaden; Department of Obstetrics and Gynecology, University Hospital Essen, Germany; Department of Hematology and Oncology, University Hospital Grosshadern, München; Wissenschaftlicher Service Pharma (WiSP), Langenfeld, Germany; Department of Hematology and Oncology, University Hospital Modena, Italy; European Group for Blood and Marrow Transplantation, University College Hospital; and the Department of Oncology, University College London, London, United Kingdom

Address reprint requests to Volker Möbus, MD, Department of Obstetrics and Gynecology, Städtisches Klinikum, Gotenstraβe 6-8, D-65929 Frankfurt, Germany; e-mail: vmoebus{at}skfh.de

	ABSTRACT

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Purpose Although ovarian cancer is one of the most chemotherapy-sensitive solid tumors, cure after radical surgery and chemotherapy is uncommon. A randomized trial comparing high-dose sequential chemotherapy with peripheral blood stem cell (PBSC) support with platinum-based combination chemotherapy was conducted to investigate whether dose-intensification improves outcome.

Patients and Methods One hundred forty-nine patients with untreated ovarian cancer were randomly assigned after debulking surgery to receive standard combination chemotherapy or sequential high-dose (HD) treatment with two cycles of cyclophosphamide and paclitaxel followed by three cycles of HD carboplatin and paclitaxel with PBSC support. HD melphalan was added to the final cycle. The median age was 50 years (range, 20 to 65 years) and International Federation of Gynecology and Obstetrics stage was IIb/IIc in 4%, III in 78%, and IV in 17%.

Results Seventy-six percent of patients received all five cycles in the HD arm and the main toxicities were neuro-/ototoxicity, gastrointestinal toxicity, and infection and one death from hemorrhagic shock. After a median follow-up of 38 months, the progression-free survival was 20.5 months in the standard arm and 29.6 months in the HD arm (hazard ratio [HR], 0.84; 95% CI, 0.56 to 1.26; P, .40). Median overall survival (OS) was 62.8 months in the standard arm and 54.4 months in the HD arm (HR, 1.17; 95% CI, 0.71 to 1.94; P, .54).

Conclusion This is the first randomized trial comparing sequential HD versus standard dose chemotherapy in first-line treatment of patients with advanced ovarian cancer. We observed no statistically significant difference in progression-free survival or OS and conclude that HD chemotherapy does not appear to be superior to conventional dose chemotherapy.

	INTRODUCTION

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Approximately one in 70 women develops ovarian cancer and 75% of patients present with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV disease. The use of platinum and taxanes have improved the median progression-free survival (PFS) and overall survival (OS) rates, which are now between 16 to 21 months and 32 to 57 months, respectively.^1-3 Although patients are surviving longer, there is no evidence that the proportion of cured patients has increased and long-term survival remains approximately 25%.

Ovarian cancer is one of the most chemotherapy-sensitive solid tumors. There is some evidence for a dose response relationship within the conventional dose range of systemic chemotherapy.^4,5 Furthermore, increasing the dose at the site of peritoneal metastases by intraperitoneal chemotherapy has been shown to improve survival.^6-8 Therefore, there is a rationale to investigate whether high-dose chemotherapy (HDC) with peripheral blood stem cell support (PBSC) improves survival.

Experience of HDC in ovarian cancer comes primarily from registry data and phase II trials in patients with recurrent disease.^9-11 These data show that response rates are very high, even in refractory and early relapsing disease, but in the vast majority of patients relapse occurs after only 3 to 9 months without evidence of a prolongation in long-term survival. More sustained responses are seen in patients with platinum-sensitive relapse and in women with small volume disease.^9,10,12 This suggests that HDC is unable to overcome resistance after previous treatment but it may be more effective in patients with platinum-sensitive disease and in the first-line setting.

Two strategies could be considered; one is to consolidate the response to conventional chemotherapy with HDC and the other is to use multicycle sequential HDC after surgery to reduce the chance of the emergence of drug resistance. High tumor responses have been seen with the latter approach.^13,14 We have shown in pilot studies^15,16 that this approach is feasible and this led us to embark on a randomized, phase III trial.

	PATIENTS AND METHODS

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Study Design
Our study is a randomized, phase III intergroup trial comparing the efficacy and safety of sequential HDC with PBSC support versus standard dose chemotherapy as first-line treatment for advanced ovarian cancer patients after surgical debulking.

The Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO)/Arbeitsgemeinschaft für Internistische Onkologie (AIO) and the European Group for Blood and Marrow Transplantation (EBMT) each launched a randomized phase III trial of HDC with PBSC support for the first-line treatment of advanced ovarian cancer in 1998. Following successful recruitment in the first 2 years, there was a sharp decline in recruitment after the negative results of HDC in breast cancer. In 2001, a jointly appointed data monitoring committee (DMC) recommended merging the two studies (AGO/AIO HD-OVAR-2 and EBMT OVCAT) that had a very similar design. In December 2001, the trial continued as the High-Dose Ovarian Cancer-European Intergroup Study (HIDOC-EIS). Separate randomization and data collection continued but a combined analysis was planned. Accrual continued until 2004 when the DMC recommended closure due to poor recruitment.

The design of both protocols was broadly similar (Fig 1). Both study groups gave two induction cycles during which PBSCs were harvested in three high-dose cycles. There were slight differences in the dose of paclitaxel and some minor differences in inclusion criteria and treatment in the conventional arm (Table 1).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Trial design of the Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO)/Arbeitsgemeinschaft für Internistische Onkologie (AIO) and the European Group for Blood and Marrow Transplantation (EBMT) study. (*) Cyclo, cyclophospamide. () Carbo, carboplatin. Carboplatin dose: area under the curve = 20.

Treatment Regimens
The protocol was based on two pilot studies.^15,16 It consisted of two cycles of intermediate dose paclitaxel (200 to 250 mg/m²) and cyclophosphamide (3 g/m²) induction therapy with PBSC harvest after the first and/or second cycle. Filgrastim was started on day 3 at a dose of 5 µg/kg and continued daily until the day of the last leukapheresis. PBSCs were harvested by standard leukapheresis protocols. At least four bags with PBSC, each containing a minimum of 2 x 10⁶ CD34-positive cells, were harvested. Each of the three high-dose courses of HDC were supported by the infusion of a minimum of 1 x 10⁶ CD34+ cells and 2 x 10⁶ CD34+ cells after the last cycle, infused 24 hours after chemotherapy and filgrastim until neutrophil counts were 0.5 x 10⁹/L. Initial chemotherapy was started within 4 to 6 weeks after surgery with induction treatment planned at 14-day intervals followed by HDC cycles planned at 21-day intervals provided that full hematologic recovery had occurred. Treatment doses are shown in Figure 1. Supportive care was delivered according to standard practice of each center.

The dose of carboplatin was calculated from the target dose (area under the curve) and the glomerular filtration rate using the Calvert formula.¹⁷ It was recommended that the glomerular filtration rate was determined by the ⁵¹CrEDTA clearance but the Jelliffe formula could be used as an alternative measure.¹⁸ Paclitaxel (200 to 250 mg/m²) was given on day 1 followed by carboplatin area under the curve of 20 on day 2. In the third high-dose cycle, melphalan (140 mg/m²) was delivered as a 20-minute infusion on day 2.

Standard chemotherapy consisted of six cycles of carboplatin/paclitaxel (carboplatin area under the curve, 5; paclitaxel 175 mg/m² over 3 hours) at 21-day intervals. Epirubicin (60 mg/m²) could be added as an option for both groups and the AGO/AIO protocol allowed consolidation treatment with four cycles of topotecan (1.25 mg/m²) on days 1 to 5.

The protocol was approved by the institutional review boards of all participating institutions and informed consent was obtained from all patients.

Statistical Considerations
In both trials, the primary outcome measure was PFS, defined as the period between random assignment and tumor progression or death as a result of any cause. Survivors were censored at the date they were last known to be alive and free of progression. Secondary end points were overall survival and toxicity of treatment. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria.

We estimated the PFS to be 35% at 2 years with standard treatment. In order to be able to detect an absolute improvement of 15% in PFS at this time point (corresponding to a hazard ratio of 0.66), with a power of 80% and a type I error of 5% using a one-tailed test (according to the one-sided nature of the study hypothesis), 208 patients needed to be recruited in a fixed sample design. This sample size was based on a requirement of a minimum follow-up of at least 2 years or up to progression. A group sequential analysis according to the spending approach by Lan and DeMets¹⁹ with an O'Brien/Fleming boundary shape²⁰ was adopted for the trial, in order to allow for an independent DMC reviewing the course of the trial.

Time to event data were analyzed using the Kaplan-Meier method, and a (stratified) log-rank test was used to compare the distributions between treatment groups. In addition, hazard ratios (HRs) with 95% CIs were estimated using the Cox proportional hazards model. All P values presented are two sided. All statistical analyses were performed using S-Plus 2000 (Statistical Sciences, Seattle, WA) and TESTIMATE version 5.2 software.

	RESULTS

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Patients
Between July 1998 and June 2004, 149 patients (89 AGO/AIO; 60 EBMT)were enrolled, representing 72% of the required population. One hundred forty-five patients were assessable for toxicity, and 146 for efficacy. One patient withdrew consent and for two patients only baseline data exist.

Baseline patient and tumor characteristics are presented in Table 2. The two treatment arms were well balanced for baseline characteristics.

Treatment Compliance
Seventy-six percent of women received all five cycles of HDC. Eighty-seven percent received four cycles and 90% received three cycles in the experimental arm. The median dose in the initial mobilization cycles and in the three high-dose cycles did not deviate from that defined by the protocol. Incomplete high-dose treatment was mostly due to adverse events (eg, neuro-/ototoxicity), severe infection, insufficient stem cell mobilization, or withdrawal of consent (one patient). Treatment delay and dose reduction were somewhat more common in the AGO/AIO group than in the EBMT group. In the standard arm, 90% of the patients received six cycles and 6% received more than six cycles. Platinum paclitaxel was given to 80% of patients. In 17%, an anthracycline was added and 3% received platinum paclitaxel followed by topotecan. Ninety-five percent of cycles in the AGO/AIO group and 98% in the EBMT group were given without dose reductions.

Toxicity
Recovery of neutrophil blood counts (> 0.5 x 10⁹/L) and platelets (> 20 x 10⁹/L) was similar after all three high-dose cycles occurring a median of 8 and 10 days, respectively. Grade 3 or 4 infection was somewhat more pronounced after the high-dose carbolated cycles than after the two induction cycles (45% v 37%). There was one treatment-related death in the high-dose arm from hemorrhagic shock secondary to upper gastrointestinal tract bleeding and acute renal failure during the aplastic phase of the fifth course of high-dose therapy. Nonhematologic toxicity is shown in Figure 2. Gastrointestinal toxicity, especially nausea, stomatitis, and oesophagitis, showed a sharp increase in the third high-dose cycle (containing melphalan), while neurologic toxicity and ototoxicity remained fairly constant.

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Nonhematologic toxicity in high-dose therapy. National Cancer Institute (NCI) grade 3 and 4 combined. (*) Includes NCI grade 2.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Progression-free survival (PFS). HD, high dose; HR, hazard ratio; FU, follow-up.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Overall survival (OS). HD, high dose; HR, hazard ratio.

	DISCUSSION

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The role of dose intensity in the chemotherapy of advanced epithelial ovarian cancer has remained a controversial issue. Small increments in the platinum dose (no greater than two-fold) have not improved survival although in some studies remission rates were higher.^4,28 There is now considerable experience of using autologous PBSCs to manage the adverse effects of HDC making it possible to test the effect of very HDC in advanced ovarian cancer.

Over the past 20 years, more than 1,000 patients have been entered into the European and American transplant registries.^9,10 Many of these patients were treated in relapse but others were treated in nonrandomized studies of HDC in the first-line setting. Case selection and retrospective reviews make interpretation of registry analyses and the nonrandomized data difficult. However, the long-term survival results from analysis of the registry data and clinical trials suggested that there might be a survival benefit from HDC.^10,12,29,30 The greatest experience is with high-dose consolidation therapy but women have also been treated with multicycle high-dose treatment after surgery.^13,15,16 The rationale for this approach is to use intensive therapy at an early stage to avoid the early emergence of drug resistance. Furthermore, multiple courses of treatment provide an opportunity of sustaining high proportion of tumor-cell kill during each cycle of treatment. Our trial was the first randomized study of multicycle HDC conducted to determine whether this intensive, toxic, and costly therapy was superior to carboplatin and paclitaxel, the standard of care.

The results of our randomized trial suggest some advantage of HDC with respect to the primary end point of PFS without achieving statistical significance (median, 29.6 months v 20.5 months; HR, 0.84; P = .4). It is very unlikely that the HR of 0.66, which was postulated prospectively and defined our original sample size, would have been reached if the sample size had been completed as planned. The relatively high PFS in the standard arm reflects the generally better prognosis of our younger patients with less than 2-cm residual disease in 88% of women and no macroscopic disease in 36% of cases. Follow-up of patients for a longer period will provide us with an adequate evaluation of survival data and long-term toxicity.

It could be argued that the total dose of platinum in the high-dose arm was still too low. Although in each cycle the platinum dose was escalated four-fold, the total dose was only twice that of the standard arm and the dose of paclitaxel in the two groups was similar. Treatment cycles were repeated after recovery of toxicity from the preceding high-dose cycle and we do not believe it would have been possible to increase the dose of platinum further. The collection of data from the two cooperative groups was different, making an analysis of the platinum dose intensity difficult. Furthermore, patients in the experimental arm received two cycles of moderately high-dose cyclophosphamide (each at 3 g/m²) and high-dose melphalan (140 mg/m²) in addition to escalated carboplatin.

Random assignment into HIDOC-EIS was at the beginning of chemotherapy and this appeared to be easier than in the consolidation studies, such as Gynecologic Oncology Group 164, which closed early due to poor accrual. However, in the French Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) trial,³¹ the control arm received further treatment at a standard dose the rate of recruitment was similar to HIDOC-EIS in the early years. Recruitment to HIDOC-EIS (and the GINECO study) was affected by the negative results of the high-dose therapy in breast cancer, and after 2000, the recruitment rate fell and the study did not reach the target accrual. Similar problems were encountered in the Finnish Ovarian Cancer Study (FINOVA) trial. Patients were randomly assigned between standard therapy with cisplatin and paclitaxel or three cycles of standard therapy followed by stem cell mobilization with cyclophosphamide and paclitaxel then high-dose carboplatin, cyclophospahmide, and mitoxantrone with PBSC rescue. The trial closed due to poor accrual after 42 patients were entered.³² However, it is unlikely that the results of HIDOC-EIS would be very different if the planned accrual had been reached.

Despite a high response rate, the failure to extend PFS and OS must reflect a failure to achieve a pathologic complete remission. Studies in which second-look surgery was performed support this view. Only 34% of patients in the study of Aghajanian et al¹³ achieved a pathologic complete remission after three cycles of high-dose carboplatin and one cycle of high-dose melphalan. In the optimally cytoreduced group, it was 55%, but a recent French study reported similar findings with 37% of patients achieving a pathologic complete remission after induction followed by two cycles of high-dose carboplatin and then dose-dense paclitaxel.³³ Similar results have been reported by Schilder et al,³⁴ after high-dose carboplatin and paclitaxel and high-dose melphalan.

The alternative strategy of using HDC as consolidation after chemotherapy and second-look surgery was investigated by Curé et al³¹ after the encouraging results from a nonrandomized trial conducted by Legros et al.¹² In this study of 110 patients, the experimental arm consisted in high-dose carboplatin and cyclophosphamide with PBSC rescue. The updated results presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004, showed no significant improvement in either PFS or OS.

We have shown that multiple cycles of HDC can be delivered safely. The patients entering the trial were younger than in most studies of ovarian cancer treatment. There was only one treatment related death in 78 patients (1.5%) and 75% of women were able to complete all five cycles. It would not have been possible to increase the intravenous platinum dose further in this study. For the remaining 18 patients (24%), treatment was stopped early due to patient choice, ototoxicity, and/or neurotoxicity. However, the large number of patients experiencing grade 3 or 4 toxicity, particularly after melphalan (Fig 2), illustrates the difficulty in delivering this type of treatment.

We performed an exploratory subgroup analysis to see if any of the known prognostic factors such as stage, grade, and residual tumor post surgery had any effect on the outcome of HDC. There was no suggestion that this was the case and we therefore conclude that intravenous high-dose multicycle chemotherapy with the drugs used in this study did not produce a superior PFS. Greater dose intensification by regional therapy may result in improvements in outcome,^6-8 but further studies of intravenous dose escalation are unlikely to be worth while in ovarian cancer.

Our phase III Intergroup trial could not confirm the encouraging results, which were reported in subgroups in earlier registry reports and phase II studies. Standard dose chemotherapy with carboplatin and paclitaxel remains the standard of care in advanced ovarian cancer. This trial does not provide evidence to support the use of HDC as first-line therapy for advanced ovarian cancer.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Volker Möbus, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, AstraZeneca, Pfizer, Roche Research Funds: Volker Möbus, Amgen, Bristol-Myers Squibb, Pfizer, Roche; Norbert Frickhofen, Amgen Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Volker Möbus, Hannes Wandt, Norbert Frickhofen, Carmelo Bengala, Rainer Kimmig, Helmut Ostermann, Jonathan A. Ledermann

Administrative support: Volker Möbus, Jonathan A. Ledermann

Provision of study materials or patients: Volker Möbus, Hannes Wandt, Norbert Frickhofen, Carmelo Bengala, Rainer Kimmig, Helmut Ostermann, Jonathan A. Ledermann

Collection and assembly of data: Volker Möbus, Kim Champion, Axel Hinke, Jonathan A. Ledermann

Data analysis and interpretation: Volker Möbus, Kim Champion, Axel Hinke, Jonathan A. Ledermann

Manuscript writing: Volker Möbus, Hannes Wandt, Jonathan A. Ledermann

Final approval of manuscript: Volker Möbus, Hannes Wandt, Norbert Frickhofen, Carmelo Bengala, Kim Champion, Rainer Kimmig, Helmut Ostermann, Axel Hinke, Jonathan A. Ledermann

	ACKNOWLEDGMENTS

 
We thank the investigators (physicians and staff) at the participating institutions on behalf of the AGO/AIO: R. Kreienberg/D. Bunjes (University Hospital, Ulm), F. Opri/W. Knauf (University Hospital Benjamin Franklin, Berlin), H. Eimermacher/W. Hatzmann/E. Schneller (Marienhospital Hagen, Marienhospital Witten, Allg. Krankenhaus Hagen), K.-O. Metz (St. Joseph-Hospital Bremerhaven), K.-H. Pflüger (Ev. Diakonie-Krankenhaus gGmbH Bremen), H. Schlosser/W. Schultze (Humaine-Klinikum Bad Saarow), M. Cierna/C. Aul (Ev Krankenhaus Bethesda Duisburg), N. Niederle/B. Lampe (Klinikum Leverkusen), A. Schneeweiss (University Hospital, Heidelberg), H. Vogt (Klinikum Kempten), E. Philipp/H.-P. Lohrmann (Klinikum Lemgo), PD W. Janni/PD C. Straka (Ludwig-Maximilians-University Hospital, Munich), A. du Bois/N. Frickhofen (Horst-Schmidt-Kliniken, Wiesbaden), U. Cirkel/H. Bodenstein (Klinikum Minden), C. Thomssen/D. Hossfeld (University Hospital, Hamburg), R. Kimmig/H. Ostermann (University Hospital Munich-Groβhadern), U. Görner/S. Rösel (Städtisches Klinikum Gütersloh), W. Kuhn/M. Sandherr (University Hospital rechts der Isar, Munich), J. Schnell/H.-J. Weh (Franziskus Hospital, Bielefeld), H. Mickan/K.-P. Maier (Städtisches Klinikum Esslingen), J. Hucke/W. Fett (Bethesda Krankenhaus Wuppertal, Praxis für Hämatologie und internistische Onkologie, Wuppertal), G. Bartzke (Kreiskrankenhaus Rottweil), D. Mühlenstedt/B. Metzner (Städt. Kliniken Oldenburg), and V. Möbus (Städtische Kliniken Frankfurt/M.-Höchst).

We thank the investigators (physicians and staff) at the participating institutions on behalf of the EBMT: T. Kozak (Charles University, Prague), P. De Jaco, C. Zamagni (Policlinico S. Orsola –Malpighi, Bologna), T. Perren (St James' University Hospital, Leeds), J. Bauer (CHU Vaudois, Lausanne), A. Casado (Hospital Universitario San Carlos, Madrid), L. Merlini (Ospedale San Bortolo, Vicenza), J. Lakota (National Cancer Institute, Bratislava), L. De Rosa (Ospedale S. Camillo-Forlanini, Rome), P. Pedrazzoli (Ospedale Niguarda Ca'Granda, Milano), J. Canon (CHNDRF, Charleroi), J. Garcia Conde (Hospital Clínico Universitario, Valencia), J.T. Fischer (Klinikum Karlsruhe gGmbH), R. Coleman (Sheffield Teaching Hospitals NHS Trust), J. Nepomuca (Thomayer Memorial Teaching Hospital, Prague), R. Ruckser (Donauspital, Wien).

We also acknowledge S. Kaye (Royal Marsden, Sutton), J. Vermorken (University Hospital Antwerpen), V. Torri (Instituto Mario Negri, Milano) as members of the Independent Data Monitoring Committee, K. Riedel (University Hospital Ulm) and N. Braganca (EBMT Trials Office, London) for their data management support, and the support of G. Rosti and T. Demirer (chairs of the EBMT Solid Tumor Working Party).

	NOTES

 
published online ahead of print at www.jco.org on August 13, 2007.

Supported by unrestricted educational grants from Amgen and Bristol-Myers Squibb.

V.M. and J.A.L. were the co-chairmen of the AGO/AIO and EBMT Intergroup.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

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

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Submitted November 22, 2006; accepted April 25, 2007.

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