Hematopoetic stem cell transplantation for solid tumors in Europe

Annals of Oncology 15: 653–660, 2004 DOI: 10.1093/annonc/mdh142 Original article Hematopoetic stem cell transplantation for solid tumors in Europe A. Gratwohl1*, H. Baldomero1, T. Demirer2, G. Rosti3, G. Dini4, R. Ladenstein5 & A. Urbano-Ispizua6 On behalf of the Accreditation Committee of the European Group for Blood and Marrow Transplantation (EBMT) in cooperation with the Working Party on Solid Tumours (STWP) and the Working Party on Pediatric Diseases (PDWP) 1 Division of Hematology, Department of Internal Medicine, Kantonsspital Basel, Switzerland; 2EBMT Office, Ankara University Medical School, Ibn-i Sina Hospital, Sihhiye, Ankara, Turkey; 3Oncology–Hematology Department, Ospedale Civile, Ravenna; 4Department of Pediatric Hematology & Oncology, Institute G. Gaslini, Genova, Italy; 5BMT Unit, St Anna Kinderspital, Vienna, Austria; 6EBMT Secretariat, Hospital Clinic, Barcelona, Spain Received 11 November 2003; accepted 23 December 2003 Background: Hematopoetic stem cell transplants (HSCT) are discussed as treatment options for patients with Introduction Intensive chemotherapy supported by hematopoietic stem cell transplantation (HSCT) has been considered a useful approach for patients with chemo-radiosensitive malignancies for many years. Hematopoetic stem cells could overcome the dose-limiting marrow toxicity of more intensive regimens [1–8]. Triggered by preliminary positive, retrospective and prospective data in the early 1990s, enthusiasm has fostered HSCT as a treatment approach for breast cancer, and transplant numbers have increased massively over several years for breast cancer and other tumors alike. This trend was supported by positive prospective randomized trials in hematological malignancies with a parallel increase in transplant numbers for lymphomas and leukemias [9–13]. A change in attitude occurred in 1997. Doubts on initial reports, failures of prospective controlled studies to document an advantage of HSCT in breast cancer, and rising awareness of the need for evidence brought about this change. HSCT numbers for breast cancer declined [14]. For other indications transplants continued, based in part on results of controlled studies, such as for neuroblastoma [15], or in the context of such studies. Definitive answers are still lacking. Optimal information is not available. Patients and treating physicians in contrast depend on an optimum of information for treatment decisions today. Large comprehensive observational databases provide an instrument to reflect current strategies. Taking the annual European Group for Blood and Marrow Transplantation (EBMT) activity survey as a basis, we therefore present a detailed analysis of current practice of HSCT for solid tumors in Europe, including changes over time in transplant numbers and differences in transplant rates between European countries over the last 12 years. The results describe current thinking of specialist teams in Europe. Patients and methods Data collection, selection and validation *Correspondence to: Dr A. Gratwohl, Division of Hematology, Department of Internal Medicine, Kantonsspital Basel, CH-4031 Basel, Switzerland. Tel: + 41-61-265-42-77; Fax: + 41-61-265-44-50; E-mail: hematology@uhbs.ch © 2004 European Society for Medical Oncology Data derived for these analyses come from the EBMT activity surveys introduced in 1990 [16]. All EBMT members and affiliated non-members receive an annual survey sheet on which they report numbers of patients by indication, stem cell source and donor type for the past year. This report includes data Downloaded from http://annonc.oxfordjournals.org/ by guest on June 25, 2015 solid tumors. Transplant numbers have changed substantially over the last decade, few controlled studies are available and different opinions prevail. Objective information on current practice is needed. Patients and methods: Data from 27 902 HSCT for solid tumors (2% allogeneic, 98% autologous), collected by the European Group for Blood and Marrow Transplantation (EBMT) activity survey from 1991 to 2002 were used to assess trends, transplant rates and coefficient of variation of transplant rates in Europe. Results: Transplant numbers increased from 536 in 1991 to 4154 in 1997 and decreased to 1913 in 2002. Indications were neuroblastoma (2504 HSCT; 9%), glioma (662 HSCT; 2%), soft tissue sarcoma (1253 HSCT; 4%), germ cell cancer (3291 HSCT; 12%), breast cancer (13 524 HSCT; 48%), Ewing’s sarcoma (1896 HSCT; 7%), lung cancer (387 HSCT; 1%), ovarian cancer (845 HSCT; 3%) and other solid tumors (3540 HSCT; 14%). Allogeneic cells were used in <20 cases up to 1997; since then allogeneic HSCT increased to 159 in 2002, mainly for renal cell carcinoma. Low coefficients of variation in transplant rates (<60%) are observed for Ewing’s sarcoma (<56.5%), suggesting consensus for this indication. Conclusions: These data give an overview on current practice of HSCT for solid tumors in Europe. They provide objective information for health-care providers and patient counselling. Key words: donor type, Europe, hematopoetic stem cell transplants, solid tumors, transplant rates 1913 27902 584 27318 3540 345 3195 2066 149 159 1754 1917 441 407 116 108 333 291 3302 4025 4154 2407 113 2294 393 73 320 43 3259 323 22 301 29 15 4139 3996 387 284 4 6 381 280 2399 3484 19 3465 402 6 396 1800 13 17 2382 1787 265 301 2 2 263 299 739 1077 9 1068 171 3 168 10 729 90 1 89 8 Total Others cross-checking with national transplant registries and onsite visits. Auto Allo Total The EBMT survey forms an integral part of a prospective quality assurance program conducted by the EBMT (http://www.ebmt.org). Validation of data includes returning a computer printout of entered data to the reporting teams, 528 Allo carcinoma has only been introduced in 2002. Auto Total new variables in 1997 (Table 1). Specific information on melanoma or renal 76 germ cell cancer, breast cancer, Ewing’s sarcoma, lung cancer, ovarian cancer and other solid tumors. Lung cancer and ovarian cancer were introduced as 2 defined and classified in 1991 as neuroblastoma, glioma, soft tissue cancer, 74 from 1991 up to and including 2002. This analysis includes solid tumors 536 654 845 29 816 100 109 8 10 92 99 104 7 97 173 1 172 188 3 185 171 0 171 n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. chose for unknown reasons not to reply, or failed to do so, despite several n.a. have increased from 143 teams in 1990 to the current status [16]. For the 2002 report, there were responses from 586 teams. Twenty-six contacted teams Allo Ovarian cancer The report is based on 636 teams from 39 European countries. The numbers Auto Total Participating countries and teams 387 1 386 1896 36 1860 13524 93 13431 3291 14 3277 Allo, allogeneic; auto, autologous; n.a., not available. 1253 25 1228 662 3 659 2504 2466 Total 38 25 42 0 0 25 42 227 261 5 3 224 256 330 512 21 14 316 491 294 326 2 2 292 324 126 109 5 7 119 104 62 51 1 0 62 50 278 279 274 2002 4 277 2001 2 63 0 63 227 4 223 824 17 807 310 3 307 141 5 136 77 1 76 268 265 2000 3 88 1 87 227 2 225 1697 15 1682 349 1 348 132 1 131 62 0 62 251 251 1999 0 87 82 0 0 87 82 200 186 2 2 198 184 2382 2629 3 8 2374 2626 350 332 1 1 349 331 151 160 0 2 149 160 67 56 1 0 67 55 256 211 250 1998 6 206 1997 5 n.a. n.a. n.a. 169 3 166 2213 4 2209 338 3 335 101 0 101 43 0 43 218 215 1996 3 n.a. n.a. n.a. n.a. n.a. n.a. 110 118 1 6 104 117 1356 845 1 9 1347 844 272 283 0 1 271 283 89 83 0 4 85 83 49 55 0 0 49 55 197 176 196 1995 1 173 1994 3 n.a. n.a. n.a. 87 0 87 400 1 399 168 0 168 67 1 66 43 0 43 141 137 4 n.a. n.a. n.a. 40 5 35 242 0 242 149 0 149 53 0 53 41 0 41 124 4 n.a. n.a. n.a. 44 3 41 94 0 94 120 0 120 41 0 Allo Lung cancer Breast cancer Total Allo Auto Germ cell Total Allo Auto Soft tissue 41 56 0 56 105 3 1993 on an Excel spreadsheet. Groups were compared with chi-square tests. 120 Mean, median and standard deviations of numerical variables were calculated 1992 Statistical analysis 102 Team density. Team densities were defined as the number of transplant teams in participating countries per 10 million inhabitants. 1991 and standard deviations as follows: CV (%) = (standard deviation/mean) × 100. Low CVs reflect little variation in transplant rates, high CVs high variation in transplant rates between the selected countries. Total to calculate the coefficient of variation (CV) of transplant rates for each disease indication. It was calculated as previously defined [17] by computing mean Allo Italy, The Netherlands, Poland, Spain, Sweden, Turkey and the UK) were used Auto 300 HSCT in 2002 (Austria, Belgium, Czech Republic, France, Germany, Glioma Coefficient of variation. Transplant rates from those countries with more than Total for all HSCT and separately for autologous and allogeneic HSCT. Population data were obtained from the US Census Office (http://www.census.gov). Neuroblastoma type and country. For each disease indication, transplant rates were assessed Auto Transplant rates. Transplant rates were defined as the number of HSCT per 10 million inhabitants. They were computed for each disease indication, donor Year cells. The information in this analysis is restricted to first transplants, e.g. refers to individual patients not to transplant numbers. Patients in planned double or triple transplant programs are counted only once. Table 1. Hematological stem cell transplants for solid tumors in Europe, 1991–2002 with the intention of replacing the existing hematopoesis by injected stem Allo Transplants. Transplants were defined by the EBMT (http://www.EBMT.org) as the infusion of hematopoetic stem cells following a conditioning regimen Auto Definitions Allo Total Ewing’s sarcoma www.annonc.oupjournals.org. Information reached us that no blood or marrow transplants were performed in Albania, Andorra, Armenia, Azerbaijan, BosniaHerzegovina, Georgia, Iceland, Liechtenstein, Malta, Moldavia, Monaco, San Marino and the Vatican during this time period. Auto Contacted teams are listed in the Appendix in alphabetical order according to country, city and EBMT center code. This can be viewed online at Total teams (3%) did not perform transplants in 2002. Allo logous, eight teams (1%) to allogeneic transplants only. Seventeen contacted Auto list. Of the 586 teams reporting HSCT in 2002, 331 (57%) do both allogeneic and autologous transplants; 230 teams (39%) restrict their activity to auto- Downloaded from http://annonc.oxfordjournals.org/ by guest on June 25, 2015 Total efforts to reach them. No major transplant team in Europe is missing from the 655 Results Trend over time Numbers and donor type of HSCT for solid tumors from 1991 to 2002 This evolution of transplant numbers over time for allogeneic and autologous HSCT is best illustrated by separation into disease subcategories (Figure 2). Different trends can be observed. There is a continuous steady increase in autologous HSCT for neuroblastoma (Figure 2A) and Ewing’s sarcoma (Figure 2B). For glioma (Figure 2A), soft tissue sarcoma (Figure 2B) and germ cell tumors (Figure 2D), numbers have been stable over the observation period. This is in sharp contrast to the evolution in breast cancer (Figure 2E), ovarian (Figure 2C) and lung cancer (Figure 2C). The increase up to 1997 is followed by a sharp decrease. For allogeneic HSCT the numbers remain low in all disease indications with the exception of other disease categories (Figure 2F). A marked increase is observed over the last 3 years and is primarily due to renal cell carcinoma (80 HSCT in 2002), breast cancer (14 HSCT in 2002) and colon cancer (nine HSCT in 2002). A total of 27 902 HSCT, 27 318 (98%) autologous and 584 (2%) allogeneic, were carried out in Europe from 1991 to 2002 (Table 1). There were 2504 HSCT for neuroblastoma (9%), 662 HSCT for glioma (2%), 1253 HSCT for soft tissue sarcoma (4%), 3291 HSCT for germ cell cancer (12%), 13 524 HSCT for breast cancer (49%), 1896 HSCT for Ewing’s sarcoma (7%), 387 HSCT for lung cancer (1%), 845 HSCT for ovarian cancer (3%), 3540 for ‘others’ (13%). The change in numbers and absolute numbers of HSCT per year for the main disease categories is presented in Table 1 and illustrated in Figure 1. There is an increase in HSCT for neuroblastoma, glioma, soft tissue sarcoma, germ cell cancer, Ewing’s sarcoma and ‘other’ indications. There is an increase initially followed by a decrease for breast cancer, lung cancer and ovarian cancer. Transplants increased 2.6-fold for neuroblastoma, 1.1-fold for glioma, 3.0-fold for soft tissue, 2.7-fold for germ cell, 3.5-fold for breast cancer (28-fold from 1991 to 1997), 5.9-fold for Ewing’s sarcoma and 5.3-fold for ‘others’ from 1991 to 2002. Primarily autologous HSCT were used for all indications with few allogeneic transplants, as presented in Table 1. Up to 10% allogeneic transplants were seen early in the 1990s for Ewing’s sarcoma with a decline thereafter. The proportion of allogeneic HSCT is increasing again in the most recent years for soft tissue sarcoma, breast cancer, ovarian cancer and ‘others’, with a total 159 allogeneic HSCT in 2002. Based on this recent increase in allogeneic HSCT for solid tumors, renal cell carcinoma and melanoma were introduced as specific new variables to the activity survey in 2002. Transplant rates in European countries Transplant rates differed markedly between European countries, as reflected by the distribution of the total 20 207 HSCT in Europe in 2002 (Figure 3). Transplant rates for all transplants (Figure 3A), including both allogeneic and autologous HSCT, varied from 0 (several countries) to more than 400 per 10 million inhabitants (several countries). The same basic difference in transplant rates between eastern and western European countries was observed if autologous transplants only were considered (Figure 3B). In addition, there was a marked over- or under-representation for certain disease indications (Figure 4). Neuroblastoma (Figure 4A), germ cell cancer and Ewing’s sarcoma (Figure 4F) were represented in similar proportions in all European countries. In contrast, some tumors, such as glioma (Figure 4B), lung cancer (Figure 4G) or ovarian cancer (Figure 4H) showed preferential distribution in Downloaded from http://annonc.oxfordjournals.org/ by guest on June 25, 2015 Figure 1. Numbers of hematopoetic stem cell transplants (HSCT) for solid tumors in Europe according to main disease categories from 1991 to 2002. Allogeneic and autologous HSCT combined. 656 Figure 3. Transplant rates in European countries, 2002. Shades reflect numbers of hematopoetic stem cell transplants (HSCT) per 10 million inhabitants. (A) All indications and all donor types. (B) Autologous HSCT. Downloaded from http://annonc.oxfordjournals.org/ by guest on June 25, 2015 Figure 2. Transplant numbers for solid tumors in Europe for 1991–2002 according to disease and donor type. (A) Neuroblastoma and glioma. (B) Ewing’s sarcoma and soft tissue sarcoma. (C) Ovarian cancer and lung cancer. (D) Germ cell tumors. (E) Breast cancer. (F) ‘Other’ solid tumors. 657 Downloaded from http://annonc.oxfordjournals.org/ by guest on June 25, 2015 Figure 4. Transplant rates for solid tumors in Europe, 2002. Shades reflect numbers of transplants for individual indications per 10 million inhabitants. Transplant rates for: (A) neuroblastoma; (B) glioma; (C) soft tissue; (D) germ cell cancer; (E) breast cancer; (F) Ewing’s sarcoma; (G) lung cancer; (H) ovarian cancer. 658 Table 2. Coefficient of variation in transplant rates for solid tumors according to disease indication in Europe 2002 Mean TR SD Ewing 4.8 2.7 Neuroblastoma 5.1 3.2 Germinal cancer 5.9 Soft tissue 2.6 Glioma Lung cancer CV Country with max. TR Country with min. TR 56.5 Italy (9.7) Turkey (0.4) 62.9 Sweden (10.1) Turkey (0.1) 4.0 68.1 Germany (16.3) Turkey (1.0) 2.7 103.6 Austria (8.5) NL, PL, S (0) 0.8 0.9 111.2 France (2.2) B, NL E, S, T (0) 0.5 0.6 127.2 Italy (1.6) CZ, NL, S, T, UK (0) Ovarian cancer 1.8 2.8 152.4 France (9.3) CZ, NL, S, T (0) Breast cancer 5.1 8.5 166.4 Italy (25.6) A, B, CZ, S, UK (0) selected countries, e.g. France for ovarian cancer or Switzerland for lung cancer. Coefficient of variation These visual differences in transplant rates for the individual disease indications were quantified by the coefficient of variation. In order to adjust for the economic impact, this analysis was restricted to 12 countries with >300 HSCT in 2002 (Table 2). They performed a total 17 237 HSCT (all indications) in 2002 with total transplant rates from 62 (Turkey) to 578 (Italy) (median 534 transplants per 10 million inhabitants). Solid tumor transplant rates differed substantially with numbers for neuroblastoma from 0.1 (Turkey) to 10.1 (Sweden) (median 5.5 per 10 million inhabitants), for glioma from 0 (several countries) to 2.2 (France) (median 0.4 per 10 million inhabitants), for soft tissue from 0 (several countries) to 8.5 (Austria) (median 2.3 per 10 million inhabitants), germ cell cancer from 1.0 (Turkey) to 16.3 (Germany) (median 4.5 per 10 million inhabitants), breast cancer from 0 (several countries) to 25.6 (Italy) (0.6 median per 10 million inhabitants), Ewing’s sarcoma from 0.4 (Turkey) to 9.7 (Italy) (median 5.3 per 10 million inhabitants), lung cancer from 0 (several countries) to 1.6 (Italy) (median 0.2 per 10 million inhabitants), ovarian cancer from 0 (several countries) to 9.3 (France) (median 0.7 per 10 million inhabitants), ‘other’ solid tumors from 1.8 (Turkey) to 22.6 (Italy) (median 7.9 per 10 million inhabitants). This variation of transplant rates, as exemplified by the CV, is listed in detail for all disease indications in Table 2. Variation is lowest for Ewing’s sarcoma (56.5) and neuroblastoma (62.9) and is highest for breast cancer (166.4) and ovarian cancer (152.4). It permits classification of disease into categories with high consensus (CV <60%), intermediate consensus (CV 55–100%) and low consensus (CV >100%) among the specialist teams concerning indications for HSCT. By using this approach, neuroblastoma and Ewing’s sarcoma could be considered as accepted indications for autologous HSCT. All other indications cannot be regarded as established indications for HSCT. Discussion These data reflect current practice of HSCT for solid tumors in Europe today, point to the changes in transplant rates over the last decade and illustrate similarities and discrepancies between European countries. They illustrate the continuing increase for some disease categories, stable situations for others, as well as increase and decrease for indications, such as breast cancer, lung cancer and germ cell tumors. In general these trends reflect the prevailing considerations of transplant physicians and specialists in the field concerning the advantage or disadvantage of HSCT: they point to consensus on the advantage of HSCT or the need for prospective studies. Stable low numbers reflect the experimental status of the procedure and decreasing numbers the advent of alternative therapies or a disadvantage of HSCT. In this context, it is comforting to see that low CVs of ≤75% coincide also with those indications where prospective randomized studies have indicated a clear advantage, i.e. neuroblastoma or Ewing’s sarcoma [15, 18–20]. Other interpretations for high CVs are possible, as illustrated by the difference in transplant rates for indications, such as lung cancer or glioma. These differences reflect the impact of the presence or absence of ongoing active study protocols by the respective national or regional study groups [21, 22]. As such, a lower transplant rate might reflect the absence and a higher transplant rate the presence of a specific national study group protocol. Little or no information exists with regard to these aspects. There are several reasons for current trends in Europe regarding autologous HSCT in solid tumors. The scenario of breast cancer deserves some specific comments or suggestions: in the early and mid-1990s impressive data from phase II trials as well as from registries accelerated the growth in number of autotransplants for this disease [1]. When the first results from phase III studies became available, a wave of pessimism began to appear and the number of patients undergoing high-dose chemotherapy began to Downloaded from http://annonc.oxfordjournals.org/ by guest on June 25, 2015 Twelve countries with >300 HSCT in 2002 (A, B, CZ, F, G, I, NL, PL, Sp, Sw, T, UK). A, Austria; B, Belgium; CV, coefficient of variation; CZ, Czech Republic; F, France; G, Germany; I, Italy; NL, The Netherlands; PL, Poland; SD, standard deviation; E, Spain; S, Sweden; T, Turkey; TR, transplant rate (see text for definitions). 659 Acknowledgements This work was supported in part by a grant from the Swiss National Research Foundation, 32-52756.97, the Swiss Cancer League, the Horten Foundation and Oncosuisse. EBMT is supported by grants from the corporate members: Amgen Europe, HoffmannLa Roche Ltd, Gilead Sciences, Baxter Oncology, Pharmacia Corporation, Chugai-Aventis, Fresenius HemoCare, SangStat, Schering AG, Gambro BCT, Elan Pharmaceuticals, Miltenyl Biotec GmbH, Therakos, Wyeth-Lederlé, Astra, Cobe International, Nextar, Liposome Co, Imtix, Octapharma, Stem Cell Technologies, ICN Pharmaceuticals and Bristol-Meyers Squibb. The cooperation of all participating teams and their staff is greatly appreciated: the EBMT secretariat (A. Urbano-Ispizua, F. McDonald), the European EBMT Data Office in Paris (V. Chesnel, N. C. Gorin), the EBMT Registry Subcommittee (P. Ljungman, C. Ruiz de Elvira), the French Registry SFGM (J. P. Jouet), the Dutch Registry TYPHON (A. Hagenbeek, A. v. Biezen, N. Tazelaar), the Austrian Registry (H. Greinix, B. Gritsch), the Italian Registry (M. Vignetti, W. Arcese, R. Oneto), the German Registry (H. Ottinger, C. Müller, B. Kubanek, N. Schmitz, U. W. Schaefer), the Swiss Registry (J. Passweg, H. Baldomero), the British Registry (K. Towlson, N. Russell), the Turkish Registry (G. Gurman, M. Arat), and the Spanish Transplantation Office (ONT) (M. Naya). The authors also thank A. Maerki for excellent secretarial assistance, as well as L. John for technical assistance with data management. References 1. Tartarone A, Romano G, Galasso R et al. Should we continue to study high-dose chemotherapy in metastatic breast cancer patients? A critical review of the published data. Bone Marrow Transplant 2003; 31: 525–530. 2. Roché H, Viens P, Biron P et al. High-dose chemotherapy for breast cancer. The French PEGASE experience. Cancer Control 2003; 10: 42–47. 3. Bergh J, Wiklund T, Erikstein B et al. Tailored fluorouracil, epirubin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomized trial. Lancet 2000; 356: 1384–1391. 4. Stadtmauer EA, O’Neill A, Goldstein LT et al. Conventional dose chemotherapy plus autologous hematopoietic stem cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 2000; 342: 1069–1075. 5. Thomas ED. Bone marrow transplantation: a review. Semin Hematol 1999; 36 (Suppl 7): 95–103. 6. Forman SJ, Blume KG, Thomas ED (eds). Hematopoietic Cell Transplantation, 2nd edition. London, UK: Blackwell Scientific 1998. 7. Craddock C. Haemopoietic stem-cell transplantation: recent progress and future promise. Lancet Oncol 2000; 227–234. 8. Urbano-Ispizua A, Schmitz N, de Witte T et al. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: definitions and current practice in Europe. Bone Marrow Transplant 2002; 29: 639–646. 9. Gratwohl A, Baldomero H, Horisberger B et al. Current trends in hematopoietic stem cell transplantation in Europe. Blood 2002; 100: 2374–2386. 10. Zittoun RA, Mandelli F, Willemze R et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’ Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 1995; 332: 217–223. 11. Uderzo C, Balduzzi A. Allogeneic bone marrow transplantation versus chemotherapy in childhood very high risk acute lymphoblastic leukemia in first complete remission: a controversial issue. Haematologica 2002; 87: 47–50. 12. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995; 333: 1540–1545. Downloaded from http://annonc.oxfordjournals.org/ by guest on June 25, 2015 drop [2–4, 14]. Most recent results remain ambiguous and the value of HSCT in breast cancer still needs to be determined in selected categories. HSCT might be an effective tool in the treatment of solid tumors in some subsets of patients [23–25]. Ninety-eight per cent of all HSCT were autologous transplants. A few allogeneic HSCT were performed in the early 1990s but then largely abandoned. Transplant-related mortality was considered to be too high despite some documented graft-versus-tumor effects. Interest was renewed with the introduction of reduced intensity conditioning transplants and the first successful reports in solid tumors [26–30]. Concepts of allogeneic HSCT for solid tumors do not rely on high-dose chemotherapy and tumor load reduction but rather on a graft-versus-tumor effect [26]. New categories of solid tumors, i.e. immunosensitive malignancies, became a target of such therapies. Focus in 1990, at the time of introduction of the EBMT activity survey, was on chemo-sensitive malignancies; hence, typically immunosensitive malignancies, such as melanoma or renal cell carcinoma, were not reported in detail but summarized as ‘others’. This has now been changed with the introduction of renal cell carcinoma, melanoma and colon cancer as subentities in the survey. Comprehensive surveys like the EBMT survey, reaching >95% of activity in the field, can provide an objective analysis of current practice [9]. By restriction to transplants, not outcome, rapid data collection can be attained on a broad basis. Only prospective randomized studies can provide evidence on outcome differences. Prospective randomized studies, however, take time. Additional years are required for data analysis and for the generation of sufficient observation time. This is specifically necessary if early events, e.g. transplant-related mortality, are offset later on by reduced relapse rate. Teams and experts in the field might change their procedure before results are known. In these situations, the EBMT activity survey has already become a standard instrument to assess transplant rates and differences between European countries. With the variation in transplant rates, difference in opinions between transplant specialists can be quantified. Data in 2002 suggest there is consensus on autologous HSCT as an indication for Ewing’s sarcoma and near consensus on neuroblastoma and germinal cancer in Europe. This present analysis does not give any data on outcome. This information is gathered elsewhere and published separately. This survey concentrates on rapid description of the current status quo. It reflects current practice of HSCT for solid tumors in Europe, gives information on consensus or dissension among specialists in the field and provides an objective basis for patient counselling and health-care planning. 660 22. 23. 24. 25. 26. 27. 28. 29. 30. the European Group for Blood and Marrow Transplantation (EBMT). Ann Oncol 2001; 12: 693–699. Rizzo JD, Williams S, Wu JT et al. Syngeneic hematopoietic stem cell transplantation for women with metastatic breast cancer. Bone Marrow Transplant 2003; 32: 151–155. Rodenhuis S, Bontenbal M, Beex LV et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 2003; 349: 7–16. Tallmann MS, Gray R, Robert NJ et al. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stemcell transplantation in high-risk breast cancer. N Engl J Med 2003; 349: 17–26. Elfenbein GJ. Stem-cell transplantation for high-risk breast cancer. N Engl J Med 2003; 349: 80–82. Slavin S. Immunotherapy of cancer with alloreactive lymphocytes. Lancet Oncol 2001; 2: 491–498. Gratwohl A, Baldomero H, Passweg J et al. Increasing use of reduced intensity conditioning transplants: report of the 2001 EBMT activity survey. Bone Marrow Transplant 2002; 30: 813–831. Feinstein L, Sandmaier B, Maloney D et al. Nonmyeloablative hematopoietic cell transplantation. Replacing high-dose cytotoxic therapy by the graft-versus-tumor effect. Ann N Y Acad Sci 2001; 938: 328–337. McSweeney PA, Niederwieser D, Shizuru JA et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400. Rizzo JD, Elias AD, Stiff PJ et al. Autologous stem cell transplantation for small cell lung cancer. Biol Blood Marrow Transplant 2002; 8: 273–280. Downloaded from http://annonc.oxfordjournals.org/ by guest on June 25, 2015 13. Attal M, Harousseau JL, Stoppa AM et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myelome. N Engl J Med 1996; 335: 91–97. 14. Twombly A. News: stem cell transplant numbers decline; research continues. J Nat Cancer Inst 2002; 117: 451–468. 15. Kletzel M, Katzenstein HM, Haut PR et al. Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol 2002; 20: 2284–2292. 16. Gratwohl A. Bone marrow transplantation activity in Europe 1990. Report from the European Group for Bone Marrow Transplantation (EBMT). Bone Marrow Transplant 1991; 8: 197–201. 17. Gratwohl A, Baldomero H, Hermans J. Quantitative assessment of consensus on indications for blood or marrow transplantation in Europe 1995. Cancer Res Ther Control 1999; 10: 123–144. 18. Pinkerton CR, Bataillard A, Guillo S. Treatment strategies for metastatic Ewing’s sarcoma. Eur J Cancer 2001; 37: 1338–1344. 19. Strother D, Ashley D, Kellie SJ et al. Feasibility of four consecutive highdose chemotherapy cycles with stem-cell rescue for patients with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor after craniospinal radiotherapy: results of a collaborative study. J Clin Oncol 2001; 19: 2696–1704. 20. Bokemeyer C, Franzke A, Hartmann JT et al. A phase I/II study of sequential, dose-escalated, high dose ifosfamide plus doxorubicin with peripheral blood stem cell support for the treatment of patients with advanced soft tissue sarcomas. Cancer 1997; 80: 1221–1227. 21. Ledermann JA, Herd R, Maraninchi D et al. High-dose chemotherapy for ovarian carcinoma: long-term results from the Solid Tumour Registry of