Rainer Souchon

Recommendations From an International Expert Panel on the Use of Neoadjuvant (Primary) Systemic Treatment of Operable Breast Cancer: An Update

Neoadjuvant (primary systemic) treatment is the standard treatment for locally advanced breast cancer and a standard option for primary operable disease. Because of new treatments and new understandings of breast cancer, however, recommendations published in 2003 regarding neoadjuvant treatment for operable disease required updating. Therefore, a second international panel of representatives of a number of breast cancer clinical research groups was convened in September 2004 to update these recommendations. As part of this effort, data published to date were reviewed critically and indications for neoadjuvant treatment were newly defined.

Phase III Postoperative Adjuvant Radiotherapy After Radical Prostatectomy Compared With Radical Prostatectomy Alone in pT3 Prostate Cancer With Postoperative Undetectable Prostate-Specific Antigen: ARO 96-02/AUO AP 09/95

PURPOSE Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Two randomized trials demonstrated an advantage for adjuvant radiotherapy (RT) compared with a wait-and-see policy. We conducted a randomized, controlled clinical trial to compare RP followed by immediate RT with RP alone for patients with pT3 prostate cancer and an undetectable prostate-specific antigen (PSA) level after RP. METHODS After RP, 192 men were randomly assigned to a wait-and-see policy, and 193 men were assigned to immediate postoperative RT. Eligible patients had pT3 pN0 tumors. Patients who did not achieve an undetectable PSA after RP were excluded from treatment according to random assignment (n = 78; 20%). Of the remaining 307 patients, 34 patients on the RT arm did not receive RT and five patients on the wait-and-see arm received RT. Therefore, 114 patients underwent RT and 154 patients were treated with a wait-and-see policy. The primary end point was biochemical progression-free survival. RESULTS Biochemical progression-free survival after 5 years in patients with undetectable PSA after RP was significantly improved in the RT group (72%; 95% CI, 65% to 81%; v 54%, 95% CI, 45% to 63%; hazard ratio = 0.53; 95% CI, 0.37 to 0.79; P = .0015). On univariate analysis, Gleason score more than 6 and less than 7, PSA before RP, tumor stage, and positive surgical margins were predictors of outcome. The rate of grade 3 to 4 late adverse effects was 0.3%. CONCLUSION Adjuvant RT for pT3 prostate cancer with postoperatively undetectable PSA significantly reduces the risk of biochemical progression. Further follow-up is needed to assess the effect on metastases-free and overall survival.

European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus group (EGCCCG): Part I

OBJECTIVES The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. METHODS Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. CONCLUSIONS Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

International Expert Panel on the Use of Primary (Preoperative) Systemic Treatment of Operable Breast Cancer: Review and Recommendations

Primary systemic therapy (PST) represents the standard of care in patients with locally advanced breast cancer. In addition, there is increasing information on PST in operable breast disease that supports the use of PST in routine practice. However, current regimens and techniques vary. To address this concern, a group of representatives from breast cancer clinical research groups in France, Germany, Italy, the United Kingdom, and the United States reviewed all available data on prospective randomized trials in this setting. Recommendations are made regarding terminology, indications, regimen, diagnosis before treatment, monitoring of efficacy, tumor localization, surgery, pathologic evaluation, and postoperative treatment.

Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer

In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377–1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478–496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497–513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.

Radiotherapy for Stages IIA/B Testicular Seminoma: Final Report of a Prospective Multicenter Clinical Trial

PURPOSE A prospective multicenter trial was initiated to evaluate the role of modern radiotherapy with reduced treatment portals for stage IIA and IIB testicular seminoma. PATIENTS AND METHODS Patients with stages IIA/B disease (Royal Marsden classification) were assessable for the trial. Staging comprised computed tomography of the chest, abdomen, and pelvis as well as analysis of tumor markers alpha-fetoprotein and beta human chorionic gonadotropin. Linac-based radiotherapy was delivered to para-aortic and high ipsilateral iliac lymph nodes. The total doses were 30 Gy for stage IIA and 36 Gy for stage IIB disease. RESULTS Between April 1991 and March 1994, 94 patients were enrolled for the trial by 30 participating centers throughout Germany. Seven patients were lost to follow-up. Median time to follow-up of 87 assessable patients was 70 months. There were 66 stage IIA and 21 stage IIB patients. One mediastinal and one field-edge relapse were observed in the stage IIA group. In the stage IIB group, there was one mediastinal and one mediastinal/pulmonary relapse. All patients were treated with a salvage regimen of platinum-based chemotherapy. Actuarial relapse-free survival at 6 years was 95.3% (95% confidence interval [CI], 88.9% to 100%) and 88.9% (95% CI, 74.4% to 100%) for stage IIA and IIB groups, respectively. Maximum acute side effects were 8% grade 3 nausea for stage IIA and 10% grade 3 nausea and diarrhea for stage IIB groups. No late toxicity was observed. CONCLUSION Radiotherapy for stages IIA/B seminoma with reduced portals yields excellent tumor control at a low rate of acute toxicity and no late toxicity, which supports the role of radiotherapy as the first treatment choice for these patients.

Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial

BACKGROUND Breast cancer with extensive axillary-lymph-node involvement has a poor prognosis after conventional treatment. In trials with historical controls, high-dose chemotherapy produced improved outcomes. We compared an intensive double-cycle high-dose chemotherapy regimen with an accelerated conventionally dosed regimen in high-risk breast cancer in a multicentre trial. METHODS Patients with at least nine positive nodes were randomly assigned either two courses of accelerated (2-week intervals, with filgrastim support), conventionally dosed epirubicin and cyclophosphamide followed by two courses of high-dose chemotherapy (epirubicin, cyclophosphamide, and thiotepa supported by peripheral-blood progenitors) or four identical cycles of epirubicin and cyclophosphamide followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil. The primary endpoint was event-free survival. Analyses were done both by intention to treat and per protocol. FINDINGS 403 patients were enrolled; 201 were assigned high-dose chemotherapy and 202 conventional treatment. The mean number of positive nodes was 17.6, and median follow-up was 48.6 months. 4-year event-free survival (intention-to-treat analysis) was 60% (95% CI 53-67) in the high-dose chemotherapy group and 44% (37-52) in the control group (p=0.00069). The corresponding overall survival was 75% (69-82) versus 70% (64-77; p=0.02). There were no treatment-related deaths. INTERPRETATION Our finding of significant improvements in both event-free and overall survival for high-dose chemotherapy compared with a dose-dense conventional regimen contrasts with the results of other studies. The discrepancy might be due partly to design differences (tandem, brief induction) between our regimen and those studied in other trials. This approach merits further study.

DEGRO practical guidelines for radiotherapy of breast cancer I: breast-conserving therapy.

Background:The present paper is an update of the practical guidelines for radiotherapy of breast cancer published in 2006 by the breast cancer expert panel of the German Society of Radiation Oncology (DEGRO) [34]. These recommendations have been elaborated on the basis of the S3 guidelines of the German Cancer Society that were revised in March 2007 by an interdisciplinary panel [18].Methods:The DEGRO expert panel performed a comprehensive survey of the literature, comprising lately published meta-analyses, data from recent randomized trials and guidelines of international breast cancer societies, referring to the criteria of evidence- based medicine [25]. In addition to the more general statements of the German Cancer Society, this paper emphasizes specific radiotherapeutic aspects. It is focused on radiotherapy after breast-conserving surgery. Technique, targeting, and dose are described in detail.Results:Postoperative radiotherapy significantly reduces rates of local recurrence. The more pronounced the achieved reduction is, the more substantially it translates into improved survival. Four prevented local recurrences result in one avoided breast cancer death. This effect is independent of age. An additional boost provides a further absolute risk reduction for local recurrence irrespective of age. Women > 50 years have a hazard ratio of 0.59 in favor of the boost. For DCIS, local recurrence was 2.4% per patient year even in a subgroup with favorable prognostic factors leading to premature closure of the respective study due to ethical reasons. For partial-breast irradiation as a sole method of radiotherapy, results are not yet mature enough to allow definite conclusions.Conclusion:After breast-conserving surgery, whole-breast irradiation remains the gold standard of treatment. The indication for boost irradiation should no longer be restricted to women ≤ 50 years. Partial-breast irradiation is still an experimental treatment and therefore discouraged outside controlled clinical trials. Omission of radiotherapy after breast-conserving surgery of DCIS should be restricted to individual exceptions.Hintergrund:Es handelt sich um ein Update der 2006 publizierten Leitlinien der Expertengruppe Mammakarzinom der Deutschen Gesellschaft für Radioonkologie (DEGRO) [34]. Diese waren in Ergänzung zur S3-Leitlinie der Deutschen Krebsgesellschaft verfasst worden, die durch ein interdisziplinäres Gremium im März 2007 überarbeitet worden war [18].Methodik:Die Expertengruppe (identisch mit den Autoren dieses Manuskripts) führte eine Literaturrecherche durch, die sämtliche neuen Metaanalysen und randomisierte Studien, die neue Gesichtspunkte gegenüber 2006 erbrachten, sowie Empfehlungen internationaler Fachgesellschaften in die Bewertung von Therapieindikationen einbezog und sich an den Kriterien evidenzbasierter Medizin orientierte [25]. In Ergänzung zu den eher generellen Statements der Deutschen Krebsgesellschaft fanden spezielle radiotherapeutische Fragestellungen besondere Berücksichtigung. Die vorliegende Arbeit beschränkt sich auf die Strahlentherapie nach brusterhaltender Operation. Technik, Zielvolumendefinition und Dosierung werden im Detail beschrieben.Ergebnisse:Die postoperative/adjuvante Bestrahlung senkt die Lokalrezidivrate. Je ausgeprägter diese Reduktion ist, umso mehr verbessert dies die Überlebensrate: Vier verhinderte Lokalrezidive vermeiden einen tumorbedingten Todesfall. Dieser Effekt ist altersunabhängig. Eine zusätzliche Boostbestrahlung senkt die Lokalrezidivrate signifikant, wobei dieser Effekt auch bei Frauen > 50 Jahre nachgewiesen wurde (Hazard-Ratio 0,59). Beim DCIS betrug die Lokalrezidivrate ohne Strahlentherapie auch bei Vorliegen günstiger Faktoren 2,4% pro Patientenjahr; eine entsprechende Studie wurde deshalb aus ethischen Gründen vorzeitig beendet. Für die Teilbrustbestrahlung liegen noch keine Langzeitergebnisse vor, die eine endgültige Bewertung erlauben.Schlussfolgerung:Weiterhin ist nach brusterhaltender Operation eines invasiven Mammakarzinoms die postoperative/adjuvante Bestrahlung der gesamten Brust unverzichtbarer Bestandteil des multimodalen Therapiekonzepts. Die Indikation zur Boostbestrahlung sollte großzügiger gestellt werden und nicht mehr nur Patientinnen bis zum 50. Lebensjahr vorbehalten sein. Die alleinige Teilbrustbestrahlung stellt nach wie vor eine experimentelle Therapie dar und sollte nicht außerhalb kontrollierter klinischer Studien erfolgen. Beim DCIS sollte nach brusterhaltender Operation nur in begründeten Ausnahmefällen auf eine Strahlentherapie verzichtet werden.

Interdisciplinary Consensus on Diagnosis and Treatment of Testicular Germ Cell Tumors: Result of an Update Conference on Evidence–Based Medicine (EBM)

Chairmanship: H.–J. Schmoll (Halle), S. Krege (Essen), R. Souchon (Hagen) Members of the Consensus Conference: AIO (Medical Oncology Working Party): PD Dr. J. Beyer (Marburg), Prof. C. Bokemeyer (Tübingen), Prof. C. Clemm* (Bad Trissl), PD Dr. H.–G. Derigs* (Mainz), PD Dr. A. Gerl (Munich), PD Dr. A. Harstrick (Darmstadt), Prof. H.–J. Schmoll (Halle), Prof. W. Siegert (Berlin), Dr. M. de Wit (Mrs.)* (Hamburg) AUO (Urooncology Working Party): PD Dr. P. Albers (Bonn), Prof. K.–P. Dieckmann (Hamburg), Dr. M. Hartmann (Hamburg), PD Dr. A. Heidenreich (Marburg), Dr. S. Kliesch (Mrs.) (Münster), PD Dr. K.U. Koehrmann (Mannheim), Dr. S. Krege (Mrs.) (Essen), PD Dr. M. Kuczyk (Hannover), Prof. P. Walz (Lüdenscheid), Dr. S. Weinknecht (Berlin), Prof. L. Weissbach (Berlin), Dr. E. Winter (Mrs.) (Schwerin), Prof. W. Hoeltl (Vienna) ARO (Radiooncology Working Party): Prof. M. Bamberg (Tübingen), Dr. J. Classen* (Tübingen), Prof. R.P. Mueller* (Cologne), PD Dr. H. Schmidberger (Göttingen), Dr. R. Souchon (Hagen) Additional participants: Prof. V. Loy* (Berlin), Prof. C. Wittekind* (Leipzig) *Cooperating members

DEGRO practical guidelines for radiotherapy of breast cancer II. Postmastectomy radiotherapy, irradiation of regional lymphatics, and treatment of locally advanced disease.

Background and Purpose:The aim of the present paper is to update the practical guidelines for radiotherapy of breast cancer published in 2006 by the breast cancer expert panel of the German Society for Radiooncology (DEGRO). These recommendations were complementing the S3 guidelines of the German Cancer Society (DKG) elaborated in 2004. The present DEGRO recommendations are based on a revision of the DKG guidelines provided by an interdisciplinary panel and published in February 2008.Methods:The DEGRO expert panel (authors of the present manuscript) performed a comprehensive survey of the literature. Data from lately published meta-analyses, recent randomized trials and guidelines of international breast cancer societies, yielding new aspects compared to 2006, provided the basis for defining recommendations referring to the criteria of evidence-based medicine. In addition to the more general statements of the DKG, this paper emphasizes specific radiooncologic issues relating to radiotherapy after mastectomy (PMRT), locally advanced disease, irradiation of the lymphatic pathways, and sequencing of local and systemic treatment. Technique, targeting, and dose are described in detail.Results:PMRT significantly reduces local recurrence rates in patients with T3/T4 tumors and/or positive axillary lymph nodes (12.9% with and 40.6% without PMRT in patients with four or more positive nodes). The more local control is improved, the more substantially it translates into increased survival. In node-positive women the absolute reduction in 15-year breast cancer mortality is 5.4%. Data referring to the benefit of lymphatic irradiation are conflicting. However, radiotherapy of the supraclavicular area is recommended when four or more nodes are positive and otherwise considered individually. Evidence concerning timing and sequencing of local and systemic treatment is sparse; therefore, treatment decisions should depend on the dominating risk of recurrence.Conclusion:There is common consensus that PMRT is mandatory for patients with T3/T4 tumors and/or four or more positive axillary nodes and should be considered for patients with one to three involved nodes. Irradiation of the lymphatic pathways and the optimal time point for onset of radiotherapy are still under debate.Hintergrund und Ziel:Ziel der Arbeit ist eine Aktualisierung der 2006 publizierten Leitlinie der „Expertengruppe Mammakarzinom“ der Deutschen Gesellschaft für Radioonkologie (DEGRO). Diese war seinerzeit in Ergänzung zur interdisziplinären S3-Leitlinie der Deutschen Krebsgesellschaft (DKG) von 2004 verfasst worden. Zwischenzeitlich erfolgten eine Überarbeitung und Aktualisierung der S3-Leitlinie der DKG, die im Februar 2008 publiziert wurde.Methodik:Die Expertengruppe (identisch mit den Autoren dieses Manuskripts) führte eine umfassende Literaturrecherche durch. Aktuelle Metaanalysen und randomisierte Studien, die neue Aspekte gegenüber 2006 ergaben, sowie Empfehlungen internationaler Fachgesellschaften wurden in die Bewertung von Therapieindikationen einbezogen. Diese orientieren sich an den Kriterien evidenzbasierter Medizin. In Ergänzung zu den eher allgemeinen Statements der DKG 2008 werden spezielle radiotherapeutische Fragestellungen behandelt, die eine Strahlentherapie nach Mastektomie (PMRT) und/oder bei fortgeschrittenen Tumoren, die Bestrahlung der Lymphabflusswege und die Sequenz von Radio- und Systemtherapie betreffen. Zielvolumendefinition und Dosierung werden im Detail beschrieben.Ergebnisse:Die PMRT senkt die Lokalrezidivrate bei Patientinnen mit hohem Rückfallrisiko (T3/T4-Tumoren und/oder befallene axilläre Lymphknoten; 12,9% mit und 40,6% ohne PMRT). Je ausgeprägter die durch die Radiotherapie bewirkte lokale Tumorkontrolle ist, desto stärker wirkt sich dies auf die Überlebenswahrscheinlichkeit aus. Bei lymphonodal positiven Patientinnen ergab sich eine absolute Verminderung der tumorspezifischen Sterblichkeit um 5,4% nach 15 Jahren. Hinsichtlich des Nutzens einer Strahlentherapie der Lymphabflusswege ist die Datenlage widersprüchlich. Eine Bestrahlung der Supraklavikularregion ist jedoch bei vier oder mehr befallenen axillären Lymphknoten stets indiziert und sollte bei ein bis drei positiven Lymphknoten erwogen werden. Bezüglich der Sequenz von Radio- und Systemtherapie gibt es keine richtungweisenden Evidenzen zugunsten einer Therapiemodalität. Postoperativ sollte die Sequenz vom dominierenden Risiko abhängig gemacht werden.Schlussfolgerung:Nach Mastektomie ist die PMRT bei T3/T4-Tumoren, Resttumor und/oder axillären Lymphknotenmetastasen obligat. Die Bestrahlung der regionalen Lymphabflusswege und die Sequenz von Radio- und Systemtherapie bleiben bei unzureichender Datenlage Gegenstand interdisziplinärer Diskussionen.