Method
SUCCESS-A study design
Primary aim of the study was a comparison of disease-free survival after
randomization of patients who received adjuvant treatment consisting of 3 cycles
of fluorouracil, epirubicin and cyclophosphamide (FEC) followed by 3 cycles of
docetaxel (D) with that of patients treated with 3 cycles of FEC chemotherapy
followed by 3 cycles of gemcitabine and docetaxel (DG), as well as a comparison
of disease-free survival after a second randomization of patients treated with
zoledronate for 2 years or 5 years respectively ([Fig. 1]). Secondary criteria were defined as: overall survival after
randomization; absence of distant metastasis; survival; toxicity; quality of
life; skeletal morbidity and the incidence of secondary cancers. The predictive
and prognostic value of minimal residual disease (MRD) in peripheral blood was
determined for translational research [9].
Fig. 1 Treatment and randomization protocol of the SUCCESS-A
trial.
Inclusion criteria were primary epithelial invasive breast cancer (pT1–4, pM0)
and histological evidence of axillary lymph node metastasis (pN1–3).
Alternatively, node-negative high-risk patients (N0/x) were included if they had
pT2 tumors, were histologic grade 3, aged > 35 or had a negative hormone
receptor status. A further criterion for inclusion in the study was R0 resection
of the primary tumor not more than 6 weeks prior to randomization.
Only physically resilient adult patients were included in the study; all patients
gave their informed consent prior to enrollment in the trial.
All inclusion and exclusion criteria were in accordance with the guidelines for
clinical oncologic trials, in particular the guidelines for the respective
chemotherapeutic agents. Treatment, therapy and monitoring were in accordance
with the statutory provisions determined by the ethics committees involved, the
BfArM (German Federal Institute for Drugs and Medical Devices) and good clinical
practice (GCP).
Questionnaire
After enrollment was completed, a questionnaire with 6 multiple choice questions
was sent to all 251 SUCCESS-A centers participating in the study. The
questionnaire investigated the following aspects ([Fig. 2]): previous participation in clinical trials; previously used
chemotherapy regimes for the same indication; changes in the intensity of care
(excluding the additional time required for the study) due to participation in
the trial; the increase in information relevant to treatment (e.g. information
obtained from the study protocol, the coordinating center of the clinical study,
the SUCCESS newsletter or study meetings); an assessment of the changes in
medical treatment and care due to recruitment into the SUCCESS-A trial, as well
as whether – after the experiences with the SUCCESS-A trial – the center would
be prepared to take part in other clinical phase III trials in future.
Fig. 2 Questionnaire on the satisfaction of the centers.
Statistical analysis
Statistical analysis was done using PASWStats17.0.2; graphs and diagrams were
created using Microsoft Office (Version 12.2.0) and Adobe Illustrator CS4
(Version 14.0.0). T-test was used for statistical analysis and p-values of
< 0.05 were considered statistically significant.
Analysis of the responses was started half a year after the questionnaires were
sent out. Completed questionnaires sent after this date were not included in the
retrospective analysis.
Results
Course of the SUCCESS-A trial
Between 1 September 2005 and 12 March 2007, 3754 patients were enrolled in the
SUCCESS-A trial. Of the 271 registered study centers, 251 (93 %) study centers
actively enrolled patients for the trial. A total of 158 patients were enrolled
every month in the first 6 months of the trial, which increased to 236 patients
per month after 12 months, and 246 patients per month at 18 months [8].
Results of the survey
In the first 3 months after the questionnaires were sent out, the response rate
for all 251 centers was 21 % (61 of 251). At the end of the predetermined
response time of half a year, 86 study centers had completed and returned the
questionnaire. Eight questionnaires had to be excluded from the analysis because
of incomplete or non-standard answers.
A total of 94 study centers (38 %) responded to the questionnaire sent out by the
study group. The centers participating in the SUCCESS-A trial were German
university hospitals, oncology practices and hospitals. An evaluation of the
centers who responded to the questionnaire showed no significant differences
with regard to the size of the participating center (number of patients with
primary breast cancer treated per year), the number of patients from the center
enrolled in the study, and the German federal state where the hospital or
medical practice was located. Nor was the response from centers that had
enrolled high numbers of patients higher compared to that of centers that had
only enrolled a single patient. It was notable that more questionnaires were
returned from university hospitals and from physicians with their own practice
than from other hospitals (40 vs. 39 vs. 35 %), although the differences were
not statistically significant.
For 40 % of the participating study centers, it was the first time they had
enrolled patients with this indication in a clinical trial.
Prior to participation of the respective center in the SUCCESS-A trial, in 46 %
(n = 36) of centers patients with this indication were treated with
anthracycline-based chemotherapy (FEC 100/120 or 4 × A/EC), patients in 50 %
(n = 39) of centers received taxane-based therapy (e.g. FEC-Doc or TAC), and
patients in 3.8 % (n = 3) of centers received CMF chemotherapy or another
chemotherapy not specified in the questionnaire.
50 % of centers reported a higher intensity of medical care (excluding the
additional time required to record the results of the study) after participating
in the SUCCESS-A trial. The other 50 % reported that the intensity of care had
remained the same. The intensity of care did not decrease in any of the
participating centers. 47 % (n = 37) of centers reported a big increase in
treatment-relevant information through their participation in the trial. A
further 46 % (n = 36) of centers reported an increase in treatment-relevant
information and only 5 centers reported no or only a limited increase in
information.
According to their own statements, after taking various factors such as oncologic
safety, side-effects and intensity of care into account, 47 % of participating
centers increased the overall quality of their medical care. In 53 % of centers,
the quality of care remained the same, and none of the survey centers reported a
decline in the overall quality of care.
In response to the question whether they would be prepared to take part in
another phase III trial after their experience with the SUCCESS-A trial, 100 %
(n = 78) of the survey centers answered in the affirmative ([Fig. 3]).
Fig. 3 Results of the survey.
Discussion
The reduction of breast cancer mortality in Western countries is one the great
success stories of scientific medicine in the past two decades [1]. Thus, further investigation of breast cancer patients is useful. A
frequently discussed and still unresolved question is whether it is permissible to
make use of patients with disease for scientific purposes and for the benefit of
future patients. Does participation in a study deflect physicians from their
intrinsic mission, namely the care of individual patients? Or does inclusion and
involvement in a larger network and a prescribed therapy regime also improve the
care given to patients?
This was the question we aimed to answer in our survey with the help of the centers
participating in the SUCCESS-A trial. With a rate of 31 % (completed and valid
questionnaires) of questionnaires returned from 251 centers, the sample was in
accordance with the response rate reported for other, similar, systematic
investigations [10].
For 40 % of centers participating in the SUCCESS-A trial, it was the first time they
had ever enrolled breast cancer patients in a clinical trial. The aim of our phase
III trial is to develop optimized tumor therapies for future use and to confirm the
benefit of these therapies using sound data obtained from a clinical trial. The
wider the range of data obtained, the more efficiently patients can be enrolled in
a
study, and the more experience a recruiting center has with clinical trials, the
quicker it is possible to obtain good quality data [10].
In the ADEBAR trial (recruitment between 2001 and 2004) which was supervised by the
same study group, for 63 % of all participating centers it was the first time they
had taken part in a clinical trial [11].
We also investigated the therapeutic benefit for the patients enrolled in the study.
Although prior to their enrollment into the SUCCESS-A trial the majority of patients
were already receiving therapy in accordance with current standards, the clinical
trial offered patients access to an innovative treatment concept tailored to
patients with these indications, and consisted of the administration of zoledronate
(4 mg/m2) for 2 or 5 years and anti-endocrine therapy with tamoxifen
and aromatase inhibitors [12]. The choice of
chemotherapeutic agents was similarly innovative: both arms of the SUCCESS-A trial
for which patients were enrolled from September 2005, were taxane-based. Half of all
participating centers had previously followed non taxane-based regimes when treating
patients with these indications. The St. Gallen Consensus of January 2005 had
already suggested that taxanes should be administered to high-risk patients, so that
a study design without taxane in both arms of the study would no longer have
complied with current standards for this high-risk collective [13]. The recommendation to additionally administer taxanes to high-risk
patients was subsequently included in the St. Gallen Consensus of 2007 [14].
The vast majority of centers reported that they had benefited from the extensive
treatment-relevant information of the study communications (e.g. study protocol,
newsletter and meetings). Based on this self-evaluation, the increase in knowledge
obtained through participating in the study was not limited to the study endpoints
but also had a positive impact on the medical care given to patients during the
trial [15]. This assumption is supported by the increase
in the intensity of care reported by the individual centers during the trial. The
centers associated the close monitoring and more intensive follow-up with the
increased time spent on documentation, while patients associated it with greater
care from their attending physician. A possible argument against enrollment in a
study is that the increased time spent on documentation could deflect attention from
patient care. The fact that a majority of centers had already previously taken part
in clinical trials has surely resulted in documentation becoming more routine; thus
the reported increase in the intensity of care is all the more remarkable. It is
also reflected in the increase in overall quality of medical care reported by 50 %
of centers. It is also astonishing in this context that not one of the centers
reported a decrease in quality due to participation in the trial.
Thus, the research into better therapies for future patients was not done at the
expense of decreasing the medical care of current patients. Quite the contrary.
Sound data showing a direct benefit of study enrollment for patients are rare.
Hébert-Croteau et al. analyzed total survival in 1727 patients with breast cancer
who were either enrolled in a clinical trial or were treated in accordance with
clinical guidelines. Multivariate analysis showed an independent total survival
benefit, despite adjusting for age, co-morbidities, grading, hormone receptor
status, tumor stage and local therapies [16].
Although the basic superiority of taxane and anthracycline-based chemotherapy
compared to anthracycline chemotherapy alone posited in our study collective will
continue to be a subject of discussion, it should be pointed out that patients in
4 % of the study centers were being treated with less effective chemotherapies and
thus were receiving treatment which did not comply with current standards. This was
improved through the participation in the study.
With our study we were able to show that patient care improves, the knowledge base
of
participating centers expands and the overall quality of care is improved by
participation in a clinical trial. All study centers reported that they were
prepared to enroll patients in clinical trials again in the future.
This is a result that fills us with pride and encourages us to continue with our
combined efforts to develop optimal therapies for patients with breast cancer.
Acknowledgements
The authors would like to thank all patients who participated in the SUCCESS-A-
trial, their families, the staff of the central study registry in Munich, and the
study centers listed below for their commitment and dedication:
Klinikum der Universität München Innenstadt, München | Praxis Dr. Ruhmland, Berlin
|
Universitätsklinikum des Saarlandes, Homburg/Saar | Gemeinschaftspraxis
Siehl/Söling, Kassel | Gemeinschaftspraxis Dr. med. Weniger/Dr. med. Bittrich,
Erfurt | Praxis Dr. Enser-Weis, Bochum | Achenbach Krankenhaus, Königs Wusterhausen
| Gemeinschaftspraxis Dr. Bojko, Dr. Abenhardt, Dr. Bosse, München |
Carl-von-Basedow-Klinikum, Merseburg | DRK – Kliniken Köpenick, Akademisches
Lehrkrankenhaus der Charité, Berlin | Pius Hospital, Oldenburg | Leopoldina
Krankenhaus Schweinfurt gGmbH, Schweinfurt | Kreiskrankenhaus Emmendingen,
Emmendingen | Hämatologische Schwerpunktpraxis Stade, Stade | Praxis Dr. Bückner,
Bochum | Gemeinschaftspraxis Dr. Forstbauer/Dr. Ziske, Troisdorf | Enzkreisklinikum,
Mühlacker | Paracelsus-Krankenhaus Ruit, Ostfildern-Ruit | Praxis Dr. Heinrich,
Fürstenwalde | Praxis Prof. Kleeberg/Dr. Engel, Hamburg | Klinikum
Kirchheim-Nürtingen, Nürtingen | Praxis Dr. Fett, Wuppertal | Städtisches Klinikum
Brandenburg, Brandenburg | Praxis Dr. Nawka, Berlin | Bethesda Krankenhaus Wuppertal
gGmbH, Wuppertal | Kreiskrankenhaus Gifhorn, Gifhorn | Marienhospital Gelsenkirchen,
Gelsenkirchen | Praxis Dr. Strotkötter, Wuppertal | Praxis Dr. Schulze
hämato-onkologische Schwerpunktpraxis, Zittau | Städtisches Klinikum St. Georg,
Leipzig | Städtisches Klinikum Rosenheim, Rosenheim | St. Elisabeth-Krankenhaus
GmbH, Köln | Klinikum der Albert-Ludwig-Universität Freiburg, Freiburg | Stadtklinik
Baden-Baden, Baden-Baden | Ev. Amalie Sieveking Krankenhaus e. V., Hamburg |
Klinikum Pforzheim GmbH, Pforzheim | Klinik Sankt Marienstift, Magdeburg |
Friederikenstift Hannover, Hannover | Praxis Dr. Gehbauer, Ingolstadt | Praxis
Dr.Kröning, Magdeburg | Südharzkrankenhaus, Nordhausen | Charité Campus
Virchow-Klinikum Universitätsmedizin Berlin, Berlin | Klinikum Obergöltzsch
Rodewisch, Rodewisch | Kreiskrankenhaus Eggenfelden, Eggenfelden | Praxis
Zimber/Brendel/Hoesl/Maintz, Nürnberg | Kreiskliniken Reutlingen GmbH, Reutlingen
|
Klinikum Kempten Oberallgäu gGmbH, Kempten | ASKLEPIOS Klinik Barmbek, Hamburg |
St. Marienhospital Vechta, Vechta | Kliniken Ludwigsburg-Bietigheim gGmbH,
Bietigheim | Brustzentrum Oberschwaben, Weingarten | Katholisches Klinikum Mainz
St. Vincenz- u. Elisabeth-Hospital, Mainz | Ev. Krankenhaus, Zweibrücken |
Universitätsfrauenklinik, Tübingen | Universitätsklinik Würzburg, Würzburg |
Kreiskrankenhaus Rottweil, Rottweil | Gemeinschaftspraxis Dr. Heine/Dr. Haessner,
Wolfsburg | Henriettenstiftung Krankenhaus, Hannover | Praxis Dr. Papke, Neustadt
(Sachsen) | Franziskus-Hospital GmbH, Bielefeld | Städt. Kliniken Esslingen,
Esslingen | Gemeinschaftspraxis Dr. Hornberger/Dr. Tanzer, Bad Reichenhall |
Klinikum Frankfurt an der Oder, Frankfurt/Oder | St. Vincenz Krankenhaus, Limburg
|
Praxis Dr. Deertz, Essen | Kreiskrankenhaus Mittleres Erzgebirge gGmbH, Zschopau |
Praxis Prof. Tesch, Frankfurt | DRK Krankenhaus, Sondershausen | Klinikum
Hoyerswerda gGmbH, Hoyerswerda | Klinikum Chemnitz gGmbH, Chemnitz | DRK
Krankenhäuser Sömmerda und Bad Frankenhausen, Sömmerda | Praxis/Klinik Drs.
Garbe/Wienecke/Mattner/Windscheid, Hamburg | Klinikum Dorothea Christiane Erxleben
Quedlinburg gGmbH, Quedlinburg | Thüringen-Klinik Georgius Agricola gGmbH, Saalfeld
| Hochwald Krankenhaus, Bad Nauheim | SRH Wald-Klinikum Gera gGmbH, Gera | Praxis
Dr. Stauch, Kronach | Caritas-Krankenhaus St. Josef, Regensburg | Klinikum Coburg,
Coburg | Klinikum St. Marien Lehrkrankenhaus der Universität Erlangen-Nürnberg,
Amberg | Praxis Dr. Gampe, Bad Windsheim, Klinikum Meiningen GmbH, Meiningen | DRK
Krankenhaus Luckenwalde, Luckenwalde | Sana-Klinikum Hof, Hof | Städtisches
Krankenhaus, Wertheim | Kreiskrankenhaus Stadthagen, Stadthagen |
Haematolgisch-onkologische Schwerpunktpraxis, Cottbus | Albertinen-Krankenhaus,
Hamburg | Klinikum Marienhospital Ruhr-Universität Bochum, Herne | Ev. Krankenhaus
Mülheim, Mülheim/Ruhr | Klinikum Landkreis Tuttlingen, Tuttlingen |
Gemeinschaftspraxis Dr. med. Hahn/Dr. med Müller, Ansbach | Johanniter Krankenhaus,
Bonn | Krankenhaus Forchheim, Forchheim | Städt. Kliniken Kassel, Kassel |
Gemeinschaftspraxis der Frauenärzte, Roth | Paracelsus-Klinik Henstedt-Ulzburg,
Henstedt-Ulzburg | Praxis Dr. Glados, Coesfeld | HELIOS-BZ Nordsachsen, Schkeuditz
|
Asklepios Klinik Bad Oldesloe, Bad Oldesloe | Kreiskrankenhaus Leonberg, Leonberg
|
Praxis Dr. Baerens, Ilsede | St. Antonius-Hospital, Eschweiler | Gemeinschaftspraxis
Dr. Göhler/Dipl. med. Dörfel, Dresden | Klinikum Garmisch-Partenkirchen GmbH,
Garmisch-Partenkirchen | Gemeinschaftspraxis Muhr am See, Muhr am See | Klinikum der
Stadt Ludwigshafen am Rhein gGmbH, Ludwigshafen | Westfälische Wilhelms
Universitätsklinik Münster | Kreiskrankenhaus Aschersleben-Staßfurt gGmbH,
Aschersleben | Kreiskrankenhaus Hameln, Hameln | Tagesklinik Altonaer Straße,
Hamburg | Asklepios Krankenhäuser GmbH Weißenfels, Weißenfels |
St. Salvator-Krankenhaus Halberstadt gGmbH, Halberstadt | Klinikum Ingolstadt,
Ingolstadt | Luisenkrankenhaus GmbH & Co. KG, Düsseldorf | Zentralklinikum gGmbH
Südthüringen, Akademisches Lehrkrankenhaus der FSU Jena, Suhl | DRK Krankenhaus
Saarlouis, Saarlouis | Ostalb-Klinikum, Aalen | Klinikum Landsberg, Landsberg |
REMS-MURR-KLINIKEN, Waiblingen | HUMAINE Vogtland Klinikum Plauen GmbH, Plauen |
Katharinen-Hospital gGmbH, Unna | Klinikum Saarbrücken gGmbH, Saarbrücken |
Praxisklinik Dr. Kittel/Dr. Klare, Berlin | Klinikum Bremerhaven Reinkenheide,
Bremerhaven | Gemeinschaftspraxis Dr. Dietz/Witte-Dietz, Salzgitter-Lebenstedt |
Gemeinschaftspraxis Dr. R. Lorenz/N. Hecker, Braunschweig | Ev. Waldkrankenhaus
Spandau, Berlin | Praxis Dr. med. Dagmar Guth, Plauen | Gemeinschaftspraxis Dr.
Kronawitter/Dr. Jung, Traunstein | Praxis Dr. Wilke, Fürth | Klinikum Fulda gAG,
Fulda | Klinikum der Friedrich-Schiller-Universität Jena, Jena | Gemeinschaftspraxis
Dr. Schönleber & Dr. Graffunder, Berlin | Gemeinschaftspraxis
Vaupel/Wolter/Robertz-Vaupel/Eßer/Schäfer-Haas, Bonn | St. Vincentius-Kliniken g AG,
Karlsruhe | Klinikum Großhadern, München | Städtisches Klinikum Lüneburg, Lüneburg
|
Kreiskrankenhaus Gummersbach GmbH, Gummersbach | Klinikum Hannover Nordstadt,
Hannover | Sächsische Schweiz Klinik Sebnitz, Sebnitz | Praxis Dr. Kalischefski,
Waldmünchen | Klinikum Ludwigsburg, Ludwigsburg | Klinikum Neumarkt, Neumarkt |
St. Johannis Krankenhaus gGmbH, Landstuhl | Praxis Dr. Elbe, Ettlingen |
Diakonissenkrankenhaus Flensburg, Flensburg | Krankenhaus St. Elisabeth und
St. Barbara, Halle | Katholisches Krankenhaus Leipzig St. Elisabeth, Leipzig |
Kreiskrankenhaus Bitterfeld/Wolfen, Bitterfeld | Klinik am Eichert, Göppingen |
Zentralklinikum Augsburg, Augsburg | Praxis Dr. Uhlig, Naunhof |
Universitätsfrauenklinik Erlangen, Erlangen | Stadtkrankenhaus Hanau, Hanau |
Klinikum Herford, Herford | Praxis Dr. Dengler/Dr. Kröber, Regensburg | Klinikum
Schwäbisch Gmünd, Mutlangen | Stadtkrankenhaus Worms gGmbh, Worms Krankenhaus
Böblingen, Böblingen | Hanse-Klinikum Strahlsund GmbH, Stralsund | Harz-Klinikum
Wernigerode-Blankenburg GmbH, Wernigerode | Praxis Dr. Schilling, Berlin | Kliniken
des Landkreises Berchtesgadener Land GmbH, Bad Reichenhall | Marienkrankenhaus
St. Wendel, St. Wendel | Amper Kliniken AG, Dachau | Robert-Bosch-Krankenhaus,
Stuttgart | Charité Campus Benjamin Franklin, Berlin | Asklepios Klinik Lich GmbH,
Lich | Klinikum Memmingen, Memmingen | Praxis Dr. Hindenburg, Berlin Städtisches
Klinikum Magdeburg, Krankenhaus Altstadt, Magdeburg | Kreiskrankenhaus Torgau,
Torgau | Caritas Klinik St. Theresia, Saarbrücken | Friedrich-Ebert-Krankenhaus
Neumünster, Neumünster | Praxis Dr. Blümel, Magdeburg | St. Franziskus-Hospital,
Ahlen | Westküstenklinikum, Heide | Süd Eifel-Kliniken Bitburg, Bitburg | St. Anna
Krankenhaus, Sulzbach-Rosenberg | Klinikum Itzehoe, Itzehoe | Klinikum Bayreuth,
Bayreuth | Praxis Dr. Mölle, Dresden | Kreiskrankenhaus Rendsburg, Rendsburg |
Universitätsfrauenklinik, Heidelberg | Georg-August-Universität Göttingen, Göttingen
| Klinikum Landshut gGmbH, Landshut | Universitätsklinik Mainz, Mainz |
Fürst-Stirum-Klinik, Bruchsal | Städt. Klinikum Karlsruhe, Akademisches
Lehrkrankenhaus der Universität Freiburg, Karlsruhe | Universitätsklinikum
Schleswig-Holstein Campus Kiel, Kiel | Universitätsklinik Carl Gustav Carus der TU
Dresden, Dresden | Praxis Dr. Doering, Bremen | Universitätsklinikum
Hamburg-Eppendorf, Hamburg | Kreiskrankenhaus Belzig GmbH, Belzig | Praxis Dr.
Vehling-Kaiser, Landshut | Helios Klinikum Berlin – Klinikum Buch, Berlin |
Helfenstein Klinik, Geislingen an der Steige | Diakonissenkrankenhaus Dessau gGmbH,
Dessau | Klinikum der Stadt Wolfsburg, Wolfsburg | Ernst-Moritz-Arndt-Universität,
Greifswald | St. Barbara-Klinik Hamm Heessen GmbH, Hamm | Krankenhaus Siloah,
Pforzheim | Kliniken Landkreis Biberach, Biberach | Praxis Dr. Laube Suhl | Praxis
Dr. Busch, Mühlhausen | Hämatologisch-onkologische Gemeinschaftspraxis,
Aschaffenburg | Praxis Dr. Müller, Leer | Praxis Dr. Seipelt, Bad Soden | Praxis Dr.
Massinger-Biebl, Waldkirchen | Evang. Diakonie Krankenhaus Bremen, Städtisches
Krankenhaus Martha-Maria Halle-Dölau gGmbH, Halle | Gemeinschaftspraxis Dr. H. Wolf
& A. Freidt, Dresden | Universitätsklinikum Schleswig-Holstein, Campus Lübeck,
Lübeck | Klinikum am Gesundbrunnen, Heilbronn | Evangelische Kliniken Gelsenkirchen
GmbH, Gelsenkirchen | Schwarzwald-Baar Klinikum Villingen-Schwenningen GmbH,
Villingen-Schwenningen | Landkreis Mittweida Krankenhaus gGmbH, Mittweida | Klinikum
Lippe-Lemgo GmbH, Lemgo | Diakoniekrankenhaus Schwäbisch-Hall, Schwäbisch-Hall |
Gemeinschaftspraxis Ardeystraße, Witten | Klinikum Nürnberg/Nord, Nürnberg |
Klinikum Fichtelgebirge, Marktredwitz | Internist. Gemeinschaftspraxis
Strauß/Rendenbach/Laubenstein, Trier | Medizinische Hochschule Hannover, Hannover
|
St. Josef Krankenhaus GmbH Moers, Moers | Gemeinschaftspraxis Dres N. Kalhori, A.
Nusch, Velbert | Praxis Dr. Reles, Berlin | Gemeinschaftspraxis Leitsmann/Lenk,
Zwickau | MAIN-KINZIG-KLINIKEN gGmbH, Krankenhaus Gelnhausen Akademisches
Lehrkrankenhaus, Gelnhausen | Diakoniekrankenhaus, Rotenburg (Wümme) | KreisKH
Delitzsch GmbH, Eilenburg | Gemeinschaftspraxis Prof. Salat/Dr. Stötzer, München |
Gemeinschaftspraxis Bohnsteen/Hendrich, Dessau | Kreiskrankenhaus, Sigmaringen |
Gemeinschaftspraxis Dr. Kappus/Dr. Schneider-Kappus, Ulm | Klinikum Konstanz,
Konstanz | Kreiskrankenhaus Ebersberg, Ebersberg | Universitätsklinikum Ulm, Ulm |
Marienhospital Brühl, Brühl | Gemeinschaftspraxis Dr. Pause/Dr. Thiel/Dr. Neuhofer,
Freising | Klinikum Weiden i. d. Oberpfalz, Weiden | Kreiskrankenhaus Schorndorf,
Schorndorf | Klinikum Südstadt, Rostock | Praxis Dr. Schlag, Würzburg | Praxis Dr.
med. Klaus Apel, Erfurt | Gemeinschaftspraxis Dr. med. Bernhard Schleicher/Peter
Schleicher, Schwandorf | Praxis Dr. Weiß, Weiden | Evangelisches Krankenhaus, Wesel
| Krankenanstalten Mutterhaus der Borromäerinnen, Trier | Universitätsklinikum
Gießen und Marburg GmbH, Marburg
