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Originally published as JCO Early Release 10.1200/JCO.2006.05.5855 on July 31 2006 © 2006 American Society of Clinical Oncology. Results of Genoidentical Hemopoietic Stem Cell Transplantation With Reduced Intensity Conditioning for Acute Myelocytic Leukemia: Higher Doses of Stem Cells Infused Benefit Patients Receiving Transplants in Second Remission or Beyond—The Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation
From the Department of Haematology and Cell Therapy; the European Group for Blood and Marrow Transplantation Acute Leukemia Working Party, Hopital Saint-Antoine Asistance Publique Hopitaux de Paris and Université Paris 6, Pierre et Marie Curie; Department of Hematology, Hopital Saint-Louis Asistance Publique Hopitaux de Paris and Uniersité Paris, Paris; Centre Hospitalo Universitaire Bordeaux, Hôpital Haut-leveque, Pessac; Hopital A. Michallon, Department of Oncology-Hematology and Université Joseph Fourier, Grenoble, France; University Hospital, Department of Hematology, Linköping, Sweden; The Oxford Radcliffe Hospital, Clinical Haematology, Oxford, United Kingdom; Hadassah University Hospital, Department of Bone Marrow Transplantation, Jerusalem; Tel-Aviv University, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Medizinische Universitaet Wien, Klinik fuer Innere Medizin I, Vienna, Austria; Policlinico San Matteo, Department of Hematology, Bone Marrow Transplantation unit, Institute for Research Against Cancers, Pavia; and the Ospedale Bergamo, Divisione di Ematologia, Bergamo, Italy Address reprint requests to Norbert-Claude Gorin, MD, PhD, Hopital Saint-Antoine, 184 rue du faubourg Saint-Antoine, Paris 75571 France; e-mail: norbert-claude.gorin{at}sat.aphp.fr
PURPOSE: Nucleated cell dose is an important and modifiable factor in hematopoietic stem cell transplantation (HSCT), however its association with outcomes in the context of reduced intensity conditioning regimen (RIC) HSCT for adults with acute myelocytic leukemia (AML) is not known. PATIENTS AND METHODS: From 1998 to 2003, 253 patients with de novo AML, received transplants with RIC and peripheral blood from a genoidentical donor. Median age was 55 years (range, 18 to 72) and the median follow-up was 17 months (range, 2 to 67). One hundred forty one patients received transplants in first remission (CR1), 47 received transplants in second remission (CR2), and 65 patients received transplants in a more advanced phase. Fludarabin-based RIC was used in 91% of patients and low-dose (< 4 Gy) total-body radiation in 23% of patients. The median nucleated and CD34 cell dose infused were 9.1x 108/kg and 5.8x 106/kg, respectively. RESULTS: Overall, 2-year leukemia-free survival (LFS) was 41% ± 4% and it was 46% ± 5% for patients receiving a higher cell dose (> 9.1x 108/kg) and 37% ± 5% for the remainders (P = .03). Higher cell doses exclusively benefited patients who received transplantations in CR2 or beyond, with LFS of 47 ± 8 versus 20 ± 8, with no detectable effect for patients who received transplants in CR1. In a multivariate analysis of the overall patient population, higher nucleated cell dose cells were associated with higher LFS (P = .04), higher incidence of chronic graft-versus-host disease (P = .01), and there was a trend towards a lower relapse incidence (P = .06). Interestingly, CD34+ cell dose was not associated with any outcomes. CONCLUSION: Nucleated cell dose is an important factor that can be modified to improve results of RIC for patients with AML transplanted later than in CR1.
Allogeneic stem-cell transplantation following myeloablative regimens, has been widely used to treat patients with acute myelocytic leukemia (AML) since the early 1970s.1-4 Several prognostic factors are however important for the outcome, age, and physical condition in particular. For patients younger than 35 years of age, a cure for leukemia can be achieved in approximately 60% of patients if the transplant is done in first remission (CR1), 40% of patients in second remission, and still 15% even in more advanced diseases.5 In contrast, older age is associated with a high (unacceptable) incidence and severity of graft-versus-host disease (GVHD) leading to high transplantation-related mortality (TRM).6 Following studies in animal models, a new modality nonmyeloablative transplant or reduced intensity conditioning (RIC) has been developed for older patients and patients with a high risk of TRM,7-16 with the argument that a less intense preparative regimen would produce less organ damage, and still enable engraftment and occurrence of graft-versus-tumor effect.17 In the past 6 years this approach has proved feasible, and the induction of graft-versus-tumor effect has indeed generated a high rate of responses. However, it remains unclear whether the reduction in antitumor activity secondary to the decrease in intensity of the preparative regimen is compensated by the graft-versus-tumor effect which in this approach is the key antitumor tool. Number of nucleated or CD34+ cells infused are important risk factors in the field of hematopoietic stem-cell transplantation independent of the type of donor (autologous or allogeneic, human leukocyte antigen [HLA] identical sibling or unrelated donor) or stem cell source (bone marrow, cord blood, or peripheral blood).18-23 With the notable exception of a study from Salamanca,24 few data, limited to small number of patients have addressed the question of the impact of cell dose in RIC transplants. Moreover, due to the possibility to modify the stem cell content, studies addressing this question are of fundamental importance. We have tested the hypothesis that nucleated or CD34 cell dose could be associated with outcomes of patients receiving an RIC transplant. Therefore, using the European Blood and Marrow database, we have selected 253 patients with AML who received an HLA identical sibling peripheral blood stem-cell transplantation using a reduced conditioning regimen in European centers from January 1998 to April 2004.
Patients The study concerned all the adult patients (n = 253) that received a RIC transplant for AML with non–T-cell depleted peripheral-blood cells from an HLA identical sibling, during the period of January 1, 1998, to May 1, 2004, and were reported to European Group for Blood and Marrow Transplantation (EBMT). An RIC was defined as preparative regimen with total body radiation (TBI) lower than 4 Gy and/or busulfan lower than 8 mg/kg (total dose) associated with or without fludarabine. The characteristics of the patient population, the disease, and the transplants are given in Table 1. The median age of the population was 54.5 years (range, 18 to 72). The distribution of the disease by French-American-British categories and by cytogenetics was as expected in the general population of AML patients. The nonmyeloablative pretransplant regimen included TBI at 2 Gy in 23% of the patients. Seventy-seven percent of patients received chemotherapy combinations, of which 91% included fludarabine. For GVHD prevention, 28% of patients received cyclosporine alone, 25% received cyclosporine plus mycophenolate mofetil, and 45% received cyclosporine plus methotrexate. Interestingly the majority of patients (56%) was transplanted in CR1 (n = 141). The follow-up for survivors was 17 months (range, 2 to 67).
End Points Acute and chronic GVHD were diagnosed and graded according to published criteria.25,26 All patients were considered assessable for acute GVHD at day +1 after transplant. Occurrence of chronic GVHD was evaluated among patients who survived with sustained engraftment from day +100 after transplant. TRM was calculated from transplantation to death related to transplant and not to relapse. Relapse was defined on the basis of morphological evidence of leukemia in bone marrow or other extra-medullary organs. Survival was calculated from transplantation to death from any cause and leukemia-free survival (LFS) was defined as time interval from transplantation to first event, either relapse or death in CR.
Statistical Analysis Cumulative incidence curves were used in a competing risks setting, death being treated as a competing event to calculate probabilities of chronic GVHD, TRM, and relapse.30 Probabilities of survival and LFS were calculated using the Kaplan-Meier estimate; the log-rank test was used for univariate comparisons. Associations of graft characteristics with outcomes were evaluated in multivariate analyses, using Cox proportional hazards for LFS and survival, and proportional subdistribution hazard regression model of Fine and Gray for other outcomes.31 All P values are two sided with type I error rate fixed at .05. Statistical analyses were performed with SPSS (version 11.5, SPSS Inc, Chicago, IL) and Splus (version 6.1, MathSoft Inc, Seattle, WA) software packages.
Overall Outcomes In the total population of patients at 2 years, the LFS was 41% ± 4%, the relapse incidence (RI) was 45% ± 3%, and the TRM was 13% ± 2%. The incidence of acute GVHD with a score of 2 or greater was 20% ± 2% and the incidence of chronic GVHD in patients living beyond day 100 was 50% ± 3%. In patients transplanted in CR1 (Figs 1 and 2), the results were 49% ± 6% for LFS, 37% ± 4% for RI, and 14% ± 3% for TRM. In patients transplanted in CR2, the results were 50% ± 8% for LFS, 34% ± 7% for RI, and 16% ± 5% for TRM. Patients who received a transplant at later stages had a poorer outcome with an LFS of 23% ± 6% (P < 10–4), an RI of 69% ± 6% (P < 10–4), and a TRM of 11% ± 3%. The incidence of acute GVHD was 19% ± 3% for CR1 patients, 32% ± 7% in CR2, and 13% ± 4% for more advanced diseases. The incidence of chronic GVHD was 52% ± 4%, 59% ± 9%, and 33% ± 8%, respectively.
Univariate Analyses for Outcomes Table 2 gives the detailed results of the univariate analyses. In addition to the status of the disease, the use of low-dose (2 Gy) TBI in the pretransplant regimen and the dose of nucleated cells infused with the graft were potentially significant factors associated with RI and LFS, respectively. In particular, regarding the doses, higher doses resulted in better LFS (46% ± 5% v 37% ± 5%; P = .03), and also a higher incidence of chronic GVHD (59% ± 5% v 41% ± 5%; P = .006) with a trend for a lower incidence of relapses (42% ± 5% v 47% ± 4%; P = .09). This in fact resulted from an effect in patients who received transplants in CR2 or beyond (LFS, 47% ± 8% v 20% ± 8%; P = .003; chronic GVHD, 62% ± 9% v 31% ± 8%; P = .006; RI, 44% ± 8% v 65% ± 7%; P = .01) with no statistically significant effect in CR1. Also, the incidence of chronic GVHD was higher with donors CMV positive by serology (51% ± 4% v 35% ± 6%; P = .05). We did not find any statistically significant impact of cytogenetics on outcome. Moreover, cytogenetics were evenly distributed in the groups of patients receiving doses in nucleated cells/kg below and above the median. Table 3 shows that other prognostic factors also were equally distributed between the two cell dose groups.
Multivariate Analyses for Outcomes Table 4 presents the results of the multivariate analyses. There was no significant risk factor selected in the statistical model which was associated with TRM.
LFS Two factors were associated with better LFS: the status of the patient at transplant (CR v more advanced) and the nucleated cell dose infused. Patients receiving doses of cells above the median had a better LFS compared with those receiving lower doses (P = .036; risk ratio [RR], 0.68; 95% CI, 0.48 to 0.98; Fig 3).
RI Status of the disease at transplant (CR v more advanced) and the pretransplant regimen (TBI v chemotherapy) were significant risk factors associated with increased RI. Patients receiving TBI at 2 Gy had a higher RI than patients receiving pretransplant regimens containing chemotherapy only (Fig 4; P = .02; RR, 1.81; 95% CI, 1.11 to 2.93). The nucleated cell dose infused was borderline significant (P = .06; RR, 0.73; 95% CI, 0.47 to 1.13) with a trend for a lower RI in those receiving the higher cell dose.
Chronic GVHD A higher nucleated cell dose was associated with an increase in the incidence of chronic GVHD.
This retrospective study concerns a series of 253 patients reported to the EBMT registry and who received transplants for AML with an HLA identical sibling, after a reduced-intensity conditioning regimen. Since RIC is still an emergent new transplant modality, this series appears at the time of this publication to be the largest available and it conveys several important pieces of information on demographics, outcome of patients, and prognostic factors among which the nature of the reduced-intensity pretransplant regimen and the cell dose infused appear important. While RIC has been originally applied to older patients and/or patients at higher risk of toxicity and TRM, usually translating into patients with more advanced disease, it is of interest in this European series that despite an expected elevated median age of 54.5 years, the range was very wide and included patients as young as 18 years of age (52 patients were younger than 45 years of age). In addition, more than 50% of the patient population received a transplant in CR1. One might conclude from this first observation that RIC has gained recognition in the treatment of AML and is being used more widely, with indications reaching younger patients and earlier stages of the disease than originally designed for. In this survey, patients who received transplants in CR1 and CR2 (Figs 1 and 2) had a similar LFS at 2 years of approximately 50%, a similar RI at approximately 35%, and a similar TRM at approximately 15%. These results suggest that RIC transplant can possibly be delayed to CR2, although this statistical finding is not necessarily easy to apply to individual patients at time of initial diagnosis or while in CR1 because in case of relapse, reaching a CR2 cannot be guaranteed. In contrast, patients who received transplants at later stages had a much worse outcome with a very high RI at approximately 70% leading to a poor LFS of only 23%. This information is valuable because, despite a considerable number of reports already published on RIC, there has been little indication on the benefit in patients with AML. With the exception of the recent multicenter retrospective study with a total of 122 patients with AML, which compared the outcome of transplants with related and unrelated donors,32 most retrospective reports have concerned small series of patients from single institutions33 and larger series, still limited, have combined various diseases.34,35 Using a genetic random assignment through a donor versus no donor comparison among 95 adult high-risk acute myeloid leukemia patients, Mohty et al36 found in an intention-to-treat analysis, that LFS and overall survival were significantly higher in the donor group who received a RIC transplant with a genoidentical donor as compared with the no donor group who received chemotherapy only. However, the key question at the present is the comparison of RIC to conventional transplants. There have been no randomized studies addressing this question, although some are being planned. A retrospective comparison has recently been done by the Acute Leukemia Working Party of the EBMT in patients older than 50 years of age.37 In this study, patients receiving an RIC had, at 2 years, a disease-free survival of 40% ± 3% and an overall survival of 47% ± 3%, which was not different from the figures found after a conventional transplant. This study, of course, was not designed to compare genoidentical allogeneic stem-cell transplants to other transplant modalities. Its goal was in fact to identify prognostic factors of RIC transplants in AML. Obviously, in addition to the short follow-up, the series presented here suffers from the usual limitation of retrospective registry studies; however, it gives a rough estimate of a possible outcome in a very heterogeneous population of patients with AML, which regroups all patients with AML receiving a nonmyeloablative stem cell transplantation since the initiation of this new transplant modality. This patient population contains a large fraction of patients who have been selected for RIC and not conventional transplant because of their age, and indeed this has been confirmed as following transplant policies of the centers in a previous EBMT survey. However, we have no indication why so many younger patients have received RIC in CR1 rather than conventional transplants and we only can assume that the medical teams had in many, if not all of them, identified adverse conditions with a higher risk of TRM. RIC transplant is not a standardized modality. Patients receiving RIC are conditioned with various pretransplant regimen, some containing TBI at 2 Gy as originally designed by the Seattle team,10 other containing chemotherapy only, which most frequently contained fludarabin as initially proposed by Slavin et al.38 The graft itself is not standardized for the dose of cells infused. When planning the analysis of prognostic factors, we were particularly interested in these two variables. Our finding that TBI alone at 2 Gy was associated with a higher RI is in agreement with the known reduced antileukemic effect of this low-dose radiation and the efficacy of fludarabin and other chemotherapeutic agents usually combined to it, such as cyclophosphamide, busulfan, or melphalan. The dose of cells infused for a transplant has long been recognized as an important parameter for outcome and a considerable number of studies in patients receiving a conventional allogeneic transplant have clearly shown that higher stem cell doses infused improve the outcome through a decrease of the TRM, and also in some studies and somewhat less expected, a reduction of RI.20-22 This RI reduction has been attributed to a graft-versus-leukemia effect mediated by higher doses of T cells in richer grafts and/or a competition effect whereby the normal hematopooietic stem cell compartment somehow refrains the leukemic clone development by other means.19,23 While the same scheme could apply to RIC, we were concerned that the situation might differ in that RIC transplant is a specific model of GVHD/graft-versus-leukemia induction with minimal antitumor effect provided by the conditioning, where there could be an optimal stem cell dose window to infuse to get a maximum graft-versus-leukemia effect with a minimum TRM resulting from GVHD.39 Recent studies in RIC transplants have shown the impact of the stem-cell graft composition on the outcome; in particular, higher numbers of CD34+ cells resulted in more rapid T-cell engraftment, higher incidence of chronic GVHD, and better survivals.40,41 This study in fact shows an interaction between the cell dose and the status of the disease at transplant: higher nucleated cell doses benefited patients transplanted in CR2 or more advanced disease, with higher LFS and lower RI. There was no detectable benefit in CR1. All prognostic factors including cytogenetics were evenly distributed. In a recent study from Salamanca24 on a smaller population of 86 patients receiving RIC for various malignancies, higher cell doses (above the 75th percentile) were infused, evaluated in CD34+/kg, and were associated with lower RI, but in high-risk patients only. Although we found an effect with the nucleated cell dose, but not with the CD34+ cell dose (Fig 5), our study shares some similarity with the report from Salamanca, and likewise suggests that infusing high-cell doses may ameliorate the negative effect of advanced disease status. Unfortunately, the registry did not contain exhaustive information and while we had information on the nucleated cell dose and the CD34+ cell dose infused, we were unable to get information on the doses of T cells. The finding that the nucleated cell dose but not the CD34+ cell dose impacted the outcome may suggest a role for the dose of T-cells infused with the graft. In this study, as in a previous EBMT studies on the impact of cell doses after conventional genoidentical allogeneic transplants for AML,20-21 we found no correlation with the incidence and severity of acute GVHD, but as already shown with peripheral blood CD 34+ doses and not with marrow a correlation with the incidence of chronic GVHD which supports the accompanying T and dendritic cell dose increase impact.42 In fact, a CD8+ dose range window for a better outcome has been reported as existing in the context of RIC, including the administration of antithymocyte globulin by the Marseille team, albeit on a much smaller patient population combining various hematological malignancies.43 Therefore, it is important to take this into account when infusing the graft.
List of institutions and physicians reporting data included in this study (Center identification code [CIC]). CIC 202, A. Gratwohl, University Hospital, Basel, Switzerland; CIC 207, E. Gluckman, Hopital St. Louis, Paris, France; CIC 207, V. Rocha, Hopital St. Louis, Paris, France; CIC 209, M.A. Boogaerts, University Hospital Gasthuisberg, Leuven, Belgium; CIC 212, O. Ringden, Huddinge University Hospital, Stockholm, Sweden; CIC 212, P. Ljungman, Huddinge University Hospital, Huddinge, Sweden; CIC 215, D.W. Bron, Institut Jules Bordet, Brussels, Belgium; CIC 217, A. Bacigalupo, Ospedale San Martino, Genova, Italy; CIC 217, F. Frassoni, Ospedale San Martino, Genova, Italy; CIC 222, B. Rio, Hotel Dieu, Paris, France; CIC 224, A.H. Goldstone, University College London Hospital, London, United Kingdom; CIC 227, H.T. Greinix, Medizinische Universitaet Wien, Vienna, Austria; CIC 231, M. Falda, Azienda Ospedaliera S. Giovanni, Torino, Italy; CIC 231, F. Locatelli, Azienda Ospedaliera S. Giovanni, Torino, Italy; CIC 232, R. Foa, Univ."La Sapienza," Rome, Italy; CIC 233, E. Deconinck, Hopital Jean Minjoz, Besancon, France; CIC 234, A. Ferrant, Cliniques Universitaires St. Luc, Brussels, Belgium; CIC 239, L.F. Verdonck, University Medical Centre, Utrecht, Netherlands, The; CIC 244, G. McQuaker, Glasgow Royal Infirmary, Glasgow, United Kingdom; CIC 246, J.J. Cornelissen, Erasmus MC-Daniel den Hoed Cancer Centre, Rotterdam, Netherlands, The; CIC 253, J.L. Harousseau, Hotel Dieu, Nantes, France; CIC 253, N. Milpied, Hotel Dieu, Nantes, France; CIC 255, T. Littlewood, The Oxford Radcliffe Hospital, Oxford, United Kingdom; CIC 258, S. Slavin, Hadassah University Hospital, Jerusalem, Israel; CIC 258, D. Engelhard, Hadassah University Hospital, Jerusalem, Israel; CIC 260, J. Sierra, Hospital Santa Creu i Sant Pau, Barcelona, Spain; CIC 261, B. Chapuis, Hopital Cantonal Universitaire, Geneva, Switzerland; CIC 265, G. Lambertenghi Deliliers, Ospedale Maggiore di Milano, Milano, Italy; CIC 267, J. Reiffers, CHU Bordeaux Hôpital Haut-leveque, Pessac, France; CIC 267, J.M. Boiron, CHU Bordeaux Hôpital Haut-leveque, Pessac, France; CIC 270, J.Y. Cahn, Hopital A. Michallon, Grenoble, France; CIC 270, F. Garban, Hopital A. Michallon, Grenoble, France; CIC 283, S. Lenhoff, University Hospital, Lund, Sweden; CIC 284, D. Milligan, Birmingham Heartlands Hospital, Birmingham, United Kingdom; CIC 286, E.P. Alessandrino, Policlinico San Matteo, Pavia, Italy; CIC 288, G. Rossi, Spedali Civili, Brescia, Italy; CIC 289, M. Brune, Sahlgrenska University Hospital, Goeteborg, Sweden; CIC 295, B. Hertenstein, Hannover Medical University, Hannover, Germany; CIC 303, K. Wilson, University of Wales, Cardiff, United Kingdom; CIC 304, A. Bosi, Ospedale di Careggi, Firenze, Italy; CIC 321, F. Lauria, Policlinico Le Scotte, Siena, Italy; CIC 331, G. Martinelli, European Institute of Oncology, Milano, Italy; CIC 344, D.J. Culligan, Grampian University Hospitals Trust, Aberdeen, United Kingdom; CIC 378, G. Saglio, University of Turin Ospedale San Luigi Orbassano, Torino, Italy; CIC 387, C. Craddock, University Hospital Birmingham NHSTrust Queen Elizabeth Medical Centre, Birmingham, United Kingdom; CIC 389, D. Niederwieser, University of Leipzig, Leipzig, Germany; CIC 392, R. Scimè, Ospedale V. Cervello, Palermo, Italy; CIC 515, T. Ruutu, Helsinki University Central Hospital, Helsinki, Finland; CIC 523, N. Gratecos, Hôpital de l'ARCHET I, Nice, France; CIC 538, A. Lange, Lower Silesian Centre for Cellular Transplantation with National Bone Marrow Donor Registry, Wroclaw, Poland; CIC 544, E.M. Pogliani, Ospedale S. Gerardo, Monza, Italy; CIC 561, A. Fassas, George Papanicolaou General Hospital, Thessaloniki, Greece; CIC 566, C. Crawley, Addenbrookes Hospital, Cambridge, United Kingdom; CIC 574, K. Indrák, University Hospital, Olomouc, Czech Republic; CIC 587, P. Iacopino, Azienda Ospedaliera Centro Unico Regionale Trapianti ‘Alberto Neri’, Reggio Calabria, Italy; CIC 588, G.J. Ossenkoppele, VU University Medical Center, Amsterdam, Netherlands, The; CIC 595, A.P. Schwarer, Alfred Hospital, Melbourne, Australia; CIC 597, J. Vorlicek, University Hospital Brno, Brno, Czech Republic; CIC 607, F. Ferrara, Cardarelli Hospital, Napoli, Italy; CIC 613, J.M. Ribera Santasusana, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; CIC 614, A.R. Zander, Hospital Universitari Germans Trias i Pujol, Hamburg, Germany; CIC 617, G. Gurman, Ibni Sina Hospital, Ankara, Turkey; CIC 617, M. Arat, Ibni Sina Hospital, Ankara, Turkey; CIC 624, M. Attal, Hopital de Purpan, Toulouse, France; CIC 640, J. Pretnar, University Med. Center, Ljubljana, Slovenia; CIC 658, T. Barbui, Ospedale Bergamo, Bergamo, Italy; CIC 666, J.H. Bourhis, Institut Gustave Roussy, Villejuif, France; CIC 671, M. Michallet, Hopital E. Herriot, Lyon, France; CIC 672, B. Lioure, Hôpital de Hautepierre, Strasbourg, France; CIC 676, P. Bordigoni, Hôpitaux de Brabois Enfants, Nancy, France; CIC 680, J. Kienast, University of Münster, Münster, Germany; CIC 692, M. Musso, Ospedale La Maddalena, Palermo, Italy; CIC 704, K. Orchard, Southampton General Hospital, Southampton, United Kingdom; CIC 713, A.E. Hunter, Leicester Royal Infirmary, Leicester, United Kingdom; CIC 717, N.H. Russell, Nottingham City Hospital, Nottingham, United Kingdom; CIC 718, V. Koza, Charles University Hospital, Pilsen, Czech Republic; CIC 725, B.V. Afanassiev, SPb State I. Pavlov Medical University, St. Petersburg, Russia; CIC 727, D. Caballero, Hospital Clínico, Salamanca, Spain; CIC 728, M.N. Fernández, Clinica Puerta de Hierro, Madrid, Spain; CIC 731, A. Wahlin, Umea University Hospital, Umea, Sweden; CIC 740, N. Theorin, University Hospital, Linköping, Sweden; CIC 754, A. Nagler, Tel-Aviv University Chaim Sheba Medical Center, Tel-Hashomer, Israel; CIC 763, G.J. Mufti, GKT School of Medicine, London, United Kingdom; CIC 766, B. Rotoli, University of Napoli "Federico II" Medical School, Napoli, Italy; CIC 778, J. Snowden, Royal Hallamshire Hospital, Sheffield, United Kingdom; CIC 780, E. Liakopoulou, Christie NHS Trust Hospital, Manchester, United Kingdom; CIC 785, J. Schubert, University Hospital of Saarland, Homburg, Germany; CIC 787, R. Andreesen, University Regensburg, Regensburg, Germany; CIC 788, A. Olivieri, Azienda Ospedali Riuniti di Ancona, Ancona (Torrette), Italy; CIC 799, A. Hellmann, Medical University of Gdansk, Gdansk, Poland; CIC 810, J. Finke, University of Freiburg, Freiburg, Germany; CIC 813, M. Bregni, Istituto Scientifico H.S. Raffaele, Milano, Italy; CIC 823, M.D. Hamon, Plymouth Hospitals NHS Trust, Plymouth, United Kingdom; CIC 825, A. Levis, S.S. Antonio e Biagio e C. Arrigo, Alessandria, Italy; CIC 941, H. Tilly, Centre Henri Becquerel, Rouen, France
The authors indicated no potential conflicts of interest.
published online ahead of print at www.jco.org on July 31, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
