1 Division of Hematology, Department of Internal Medicine, Kantonsspital Basel, Switzerland; 2 EBMT Office, Ankara University Medical School, Ibn-i Sina Hospital, Sihhiye, Ankara, Turkey; 3 OncologyHematology Department, Ospedale Civile, Ravenna; 4 Department of Pediatric Hematology & Oncology, Institute G. Gaslini, Genova, Italy; 5 BMT Unit, St Anna Kinderspital, Vienna, Austria; 6 EBMT Secretariat, Hospital Clinic, Barcelona, Spain
Received 11 November 2003; accepted 23 December 2003
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ABSTRACT |
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Hematopoetic stem cell transplants (HSCT) are discussed as treatment options for patients with 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%), Ewings 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 Ewings 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
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Introduction |
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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.
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Patients and methods |
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Participating countries and teams
The report is based on 636 teams from 39 European countries. The numbers 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 chose for unknown reasons not to reply, or failed to do so, despite several efforts to reach them. No major transplant team in Europe is missing from the list. Of the 586 teams reporting HSCT in 2002, 331 (57%) do both allogeneic and autologous transplants; 230 teams (39%) restrict their activity to autologous, eight teams (1%) to allogeneic transplants only. Seventeen contacted teams (3%) did not perform transplants in 2002.
Contacted teams are listed in the Appendix in alphabetical order according to country, city and EBMT center code. This can be viewed online at www.annonc.oupjournals.org. Information reached us that no blood or marrow transplants were performed in Albania, Andorra, Armenia, Azerbaijan, Bosnia-Herzegovina, Georgia, Iceland, Liechtenstein, Malta, Moldavia, Monaco, San Marino and the Vatican during this time period.
Definitions
Transplants. Transplants were defined by the EBMT (http://www.EBMT.org) as the infusion of hematopoetic stem cells following a conditioning regimen with the intention of replacing the existing hematopoesis by injected stem 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.
Transplant rates. Transplant rates were defined as the number of HSCT per 10 million inhabitants. They were computed for each disease indication, donor type and country. For each disease indication, transplant rates were assessed for all HSCT and separately for autologous and allogeneic HSCT. Population data were obtained from the US Census Office (http://www.census.gov).
Coefficient of variation. Transplant rates from those countries with more than 300 HSCT in 2002 (Austria, Belgium, Czech Republic, France, Germany, Italy, The Netherlands, Poland, Spain, Sweden, Turkey and the UK) were used to calculate the coefficient of variation (CV) of transplant rates for each disease indication. It was calculated as previously defined [17] by computing mean and standard deviations as follows: CV (%) = (standard deviation/mean) x 100. Low CVs reflect little variation in transplant rates, high CVs high variation in transplant rates between the selected countries.
Team density. Team densities were defined as the number of transplant teams in participating countries per 10 million inhabitants.
Statistical analysis
Mean, median and standard deviations of numerical variables were calculated on an Excel spreadsheet. Groups were compared with chi-square tests.
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Results |
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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, Ewings 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 Ewings sarcoma and 5.3-fold for others from 1991 to 2002.
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Trend over time
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 Ewings 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).
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Discussion |
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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 drop [24, 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 [2325].
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 [2630]. 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 Ewings 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.
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Acknowledgements |
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FOOTNOTES |
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