Lothar Weißbach

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.

ORGAN SPARING SURGERY FOR MALIGNANT GERM CELL TUMOR OF THE TESTIS

PURPOSE We evaluate the indication, technique and long-term outcome of organ preserving tumor resection rather than standard orchiectomy in 73 patients with bilateral testicular germ cell tumors or tumors of a solitary testicle. MATERIALS AND METHODS Tumor resection was performed in 73 patients with 52 and 17 metachronous and synchronous bilateral testicular germ cell tumors, respectively, and 4 testicular germ cell tumors of a solitary testicle. Histology of the enucleated germ cell tumor revealed seminoma in 42 (57.5%) patients, embryonal carcinoma in 14 (19.2%), mature teratoma in 11 (15.1%), and mixed and combined germ cell tumors in 6 (8.2%). Mean tumor diameter was 15 mm. (range 5 to 30). Associated testicular intraepithelial neoplasia was diagnosed in 82% of patients who underwent local radiation with 18 Gy. RESULTS After a median followup of 91 months (range 3 to 191) 72 (98.6%) patients had no evidence of disease and 1 died of systemic tumor progression. No local relapse occurred in 46 patients with associated testicular intraepithelial neoplasia treated with local radiation. However, local recurrence did develop in 4 patients after 3, 6, 12 and 165 months without radiation but all survived after undergoing inguinal orchiectomy. Testosterone levels were normal in 62 (84.9%) patients, hypogonadism developed in 7 (9.6%) and preoperative levels remained low in 4 (5.5%). Of the 10 patients who postponed local radiation for paternity reasons 5 had successfully fathered a child after organ sparing surgery. CONCLUSIONS After a long-term followup of greater than 7 years organ sparing surgery represents a viable therapeutic approach to bilateral testicular germ cell tumor with an excellent postoperative outcome. Tumor enucleation might be considered a standard approach if the guidelines are respected, including cold ischemia, organ confined tumor less than 20 mm., multiple biopsies of the tumor bed, adjuvant local irradiation postoperatively to avoid local recurrence, close followup and high compliance.

Regional Hyperthermia in Conjunction with Definitive Radiotherapy against Recurrent or Locally Advanced Prostate Cancer T3 pN0 M0

Background and Purpose:Since long-term results of the standard treatment of locally advanced or recurrent prostatic carcinoma are unsatisfactory, the role for additional regional hyperthermia was evaluated in a phase I/II study.Patients and Methods:From 08/1996 to 03/2000, 22 patients were treated by a standard irradiation regimen (68.4 Gy) in combination with regional hyperthermia (weekly, five to six times), and five of 22 patients received short-term (neoadjuvant) hormonal treatment. Of these, 15 patients had primary prostatic carcinoma T3 pN0 M0 and seven a histologically confirmed local recurrence after radical prostatectomy. Feasibility of hyperthermia, and acute/late toxicity as well as long-term follow-up (prostate- specific antigen [PSA] control, overall survival) were analyzed. Clinical endpoints were correlated with thermal parameters.Results:Mean maximum temperatures along the urethra of 41.4 °C (41.0 °C for the recurrences), and mean T90 values of 40.7 °C could be achieved. Severe acute toxicity of grade 3 occurred at the rectum in three, at the urethra in four, at the intestine in one, and a burn induced by hyperthermia in one of 22 patients. Late toxicity was only observed rectally in one patient (grade 3) and at the urethra in two patients (grade 2). There was no correlation between thermal parameters and any toxicity. The survival curves showed a PSA control for primary prostatic carcinoma > 50% after 6 years, but no long-term PSA control for the recurrences. Overall survival after 6 years was 95% for primary carcinoma, and 60% for the recurrences. There was a clear correlation between higher temperatures or thermal doses with long-term PSA control.Conclusion:Regional hyperthermia might be a low-toxicity approach to increase PSA control of common treatment schedules. Further evaluation, in particular employing improved hyperthermia technology, is worthwhile.Hintergrund und Ziel:Die Langzeitergebnisse der Standardtherapie beim lokal fortgeschrittenen oder rezidivierten Prostatakarzinom sind unbefriedigend. Daher wurde eine zusätzliche regionale Hyperthermie in einer Phase-I/II-Studie evaluiert.Patienten und Methodik:Von 08/1996 bis 03/2000 wurden 22 Patienten mit einer Standardradiotherapie von 68,4 Gy in Kombination mit regionaler Hyperthermie (wöchentlich, fünf bis sechs Sitzungen) behandelt. Bei fünf von 22 Patienten wurde eine neoadjuvante Hormonbehandlung durchgeführt. Bei 15 Patienten lag ein primäres Prostatakarzinom T3pN0M0 vor; sieben Patienten hatten ein histologisch bestätigtes Lokalrezidiv nach radikaler Prostatektomie. Geprüft wurden die Durchführbarkeit der Hyperthermie, die akute und späte Toxizität sowie die Langzeitkontrolle (PSA-Kontrolle [prostataspezifisches Antigen], Gesamtüberleben). Die klinischen Endpunkte wurden mit thermischen Parametern korreliert.Ergebnisse:Es konnten mittlere Maximaltemperaturen entlang der Urethra von 41,4 °C (41,0 °C für die Rezidive) sowie mittlere T90 von 40,7 °C erreicht werden. Schwere akute Nebenwirkungen vom Grad 3 traten am Rektum bei drei, an der Urethra bei vier, am Dünndarm bei einem sowie durch Hyperthermie bedingt (Verbrennung) bei einem von 22 Patienten auf. Spätfolgen wurden nur bei einem Patienten am Rektum (Grad 3) und bei zwei Patienten an der Urethra (Grad 2) festgestellt. Es bestand keine Korrelation zwischen thermischen Parametern und irgendeiner Toxizität. Die Überlebenskurven zeigten eine PSA-Kontrolle von > 50% beim primären Prostatakarzinom nach 6 Jahren, jedoch keine Langzeit-PSA-Kontrolle bei den Rezidiven. Das Gesamtüberleben betrug nach 6 Jahren 95% für die primären Prostatakarzinome und 60% für die Rezidive. Es fand sich eine deutliche Korrelation zwischen hohen Temperaturen bzw. thermischen Dosen und der langfristigen PSA-Kontrolle.Schlussfolgerung:Die regionale Hyperthermie könnte eine gut verträgliche Zusatztherapie sein, um die PSA-Kontrolle von üblichen Therapieschemata zu verbessern. Hier ist eine weitere Evaluation sinnvoll, insbesondere auch unter Anwendung verbesserter Hyperthermietechnologien.

Development of the Interdisciplinary Evidence-Based S3 Guideline for the Diagnosis and Treatment of Prostate Cancer: Methodological Challenges and Solutions

Evidence-based guidelines are important sources of knowledge in everyday clinical practice. In 2005, the German Society for Urology decided to develop a highquality evidence-based guideline for the early detection, diagnosis and treatment of the different clinical manifestations of prostate cancer. The guideline project started in 2005 and involved 75 experts from 10 different medical societies or medical organizations including a patient organization. The guideline was issued in September 2009 and consists of 8 chapters, 170 recommendations, and 42 statements. Due to the broad spectrum of clinical questions covered by the guideline and the high number of participating organizations and authors, the organizers faced several methodological and organizational challenges. This article describes the methods used in the development of the guideline and highlights critical points and challenges in the development process. Strategies to overcome these problems are suggested which might be beneficial in the development of new evidence-based guidelines in the future.

Interdisziplinäre Konsensus-Konferenz zur Diagnostik und Therapie von Hodentumoren

1988 grundeten fuhrende Wissenschaftler auf den Gebieten Urologie, internistische und Radioonkologie eine Deutsche Arbeitsgruppe „Hodentumoren”. Seitdem hat die Arbeitsgruppe mehrere klinische Studien und Konferenzen initiiert mit dem Ziel, aktuelle Standards der Behandlung von Hodentumoren zu definieren. Nach einer Reihe von vorbereitenden Sitzungen der Vertreter der AUO, AIO und ARO der Deutschen Krebsgesellschaft wurde im Mai 1996 eine Konsensus-Konferenz uber Diagnose und Behandlung von Hodentumoren abgehalten.

A paradigm shift. Defensive strategies for the treatment of localized prostate cancer in the new S3 guideline

ZusammenfassungDurch die PSA-gestützte Früherkennung werden immer mehr Karzinome entdeckt, die ohne Screening unerkannt geblieben wären. Vor diesem Hintergrund gewinnen defensive Strategien an Bedeutung. Die aktuelle S3-Leitlinie trägt dieser Entwicklung Rechnung, indem sie „active surveillance“ (AS) und „watchful waiting“ (WW) als gleichberechtigte Therapieoptionen beim lokal begrenzten Prostatakarzinom empfiehlt. Die verfügbaren Daten zu AS, auf denen die Leitlinienempfehlungen beruhen, weisen darauf hin, dass es sich für eine definierte Patientenklientel mit Tumoren geringen Risikoprofils um eine sichere Therapieoption handelt. Dennoch sind in der Praxis die Vorbehalte gegen defensive Strategien hoch, obwohl eine kurative Maßnahme bei Patienten mit Low-risk-Tumoren von geringem therapeutischem Nutzen ist.AbstractEarly detection based on measurement of the prostate-specific antigen (PSA) has resulted in more cases of prostate cancer being discovered that would have remained unnoticed without screening. Against this background, defensive strategies gain in importance. The current S3 guideline takes this development into account by recommending “active surveillance” (AS) and “watchful waiting” (WW) as equally accepted treatment options for localized prostate cancer. The available data concerning AS, on which the guideline recommendations rely, indicate that it is a safe treatment option for a well-defined patient cohort with low-risk tumors. Nevertheless, defensive strategies are regarded with considerable reservation in clinical practice, although curative measures in patients with low-risk tumors are of little therapeutic value.

Interdisziplinäre Konsensus-Konferenz zur „Diagnostik und Therapie von Hodentumoren”@@@Interdisciplinary consensus conference on “diagnosis and treatment of germ cell tumors”

Zusammenfassung1988 gründeten führende Wissenschaftler auf den Gebieten Urologie, internistische und Radioonkologie eine Deutsche Arbeitsgruppe „Hodentumoren”. Seitdem hat die Arbeitsgruppe mehrere klinische Studien und Konferenzen initiiert mit dem Ziel, aktuelle Standards der Behandlung von Hodentumoren zu definieren. Nach einer Reihe von vorbereitenden Sitzungen der Vertreter der AUO, AIO und ARO der Deutschen Krebsgesellschaft wurde im Mai 1996 eine Konsensus-Konferenz über Diagnose und Behandlung von Hodentumoren abgehalten.Die Standards, auf die man sich bei der Konferenz einigte, beziehen sich auf die aktuelle internationale Literatur und geben Empfehlungen für die meisten klinischen Situationen. Behandlungsstrategien, die von diesen Standards abweichen, sollten nicht angewandt werden mit Ausnahme von gut begründbaren Einzelfällen oder Patienten in klinischen Studien.Kein Konsens konnte gefunden werden für nichtseminomatöse Hodentumoren der Stadien I, IIA und IIB. Deshalb werden die unterschiedlichen Behandlungsstrategien für diese Stadien in dem Beitrag wiedergegeben. Eine Nachfolgekonferenz in den kommenden Jahren ist notwendig, um zu einer möglichen Übereinkunft für diese Tumorstadien zu kommen und die derzeitigen Standards nach neuen klinischen Erfahrungen und Erkenntnissen zu überarbeiten.AbstractIn 1988 the German testicular working group was set up by leading experts in the fields of urology, medical- and radiooncology. Since then, the working group has initiated several clinical studies and conferences with the aim of defining current standards in the treatment of testicular germ cell tumours. After a series of preliminary joint meetings with representatives from the AUO, AIO and ARO of the “Deutsche Krebsgesellschaft”, a conference was held in May 1996 to agree on a consensus in diagnosis and treatment of testicular germ cell tumours.The standards which have been agreed on at the conference refer to the current international literature and provide recommendations for the majority of clinical situations. Treatment strategies differing from these standards should not be chosen except for well argued individual settings or patients treated in clinical trials.No consensus could be reached for nonseminomatous stage I, IIA and IIB tumours. As a consequence, the differing treatment strategies for these stages are summarized in this paper. A subsequent conference in later years is needed to possibly find an agreement for these tumour stages and to update the current standards according to new clinical experience and knowledge.

Changing concepts in early cancer detection.

least the legislation. We are still miles away from being able to give expert advice on all open questions surrounding the law on early cancer detection (Krebsfruherkennungsund -registergesetz, KFRG). These include: definition of the target population; appropriate procedures; intervals of testing; riskadapted early diagnosis; and adequate obligatory information. This much is certain, opportunistic screening that lacks evaluation must end. Public relations events and campaigns may succeed in raising demand but fail to enable truly informed consent. We require fora in order to arrive at a public consent that will inform and capacitate our political decision makers. What does the reader think about the changing concept of early cancer detection? Looking forward to a lively discussion, Karger Verlag is ready to publish reactions in the form of ‘Letters to the Editor’. The database of early detection of prostate cancer is, unfortunately, inhomogeneous, thus providing a battleground for diverse interpretations that are not driven only by intellectual scrutiny but by professional attitudes and individual interests. With the editors’ plan to sharpen the picture by presenting a Pro and Contra tableau, it was easy enough to find experts ready to argue in favour of early detection. More than just a few raised their eyebrows when the respective opponents and commentators were named, and the ensuing debate was not entirely free from personal controversy. Hoping, however, to spark a wider factual discussion amongst the readers, we like to thank all contributors for their readiness to deal with this complex matter. The beneficiaries of more and more differentiated information will be concerned individuals, the public, and last but not

Title Page / Contents / Imprint

S. Al-Batran, Frankfurt/M. C. Berking, München C. Bokemeyer, Hamburg M. Borner, Bern T. Cerny, St. Gallen H. T. Eich, Münster A. Engert, Köln M. Fassnacht, Würzburg B. Groner, Frankfurt/M. V. Heinemann, München M. Hentrich, München R. D. Issels, München W. Janni, Ulm U. R. Kleeberg, Hamburg H. Lang, Mainz M. Moehler, Mainz M. Schuler, Essen R. Stupp, Zürich M. Theobald, Mainz R. Thomas, Köln U. Wedding, Jena J. A. Werner, Marburg O. Zivanovic, New York

Decisions about cancer screening - based on beliefs or facts?

Accessible online at: www.karger.com/ort Fax +49 761 4 52 07 14 Information@Karger.com www.karger.com Decisions about Cancer Screening – Based on Beliefs or Facts? cannot be answered. It is striking that this ambiguity is not reflected in health policies and the public debate. Although the German National Cancer Plan opts for ‘informed’ decisions, it declares as a principal goal that adherence to screening programs is to be improved [8]. Campaigns are run to encourage people to undergo screening rather than to get informed and make their own decisions on the basis of the best available evidence. Both, physicians and the public have very positive perceptions of cancer screening [9, 10]. Many women even believe that mammography can prevent breast cancer [10]. One possible explanation may be derived from the Wilson and Jungner criteria for screening tests [6]. Criterion number 7 demands that ‘the natural history of the condition, including development from latent to declared disease, should be adequately understood’. In fact, we only have a poor understanding of the natural history of cancer and hardly any data available on untreated cancer, as we presume it is unethical not to offer curative treatment to cancer patients. Our understanding of cancer still goes back to the definition by pathologist Rudolf Virchow 150 years ago, who had made his observations on people dying from cancer and concluded that every disease showing the same pathological patterns would equally lead to death. From this point of view, every treated cancer not resulting in death was a success due to treatment. Today, we have specific instruments to detect small cancers in asymptomatic people. The phenomenon of overdiagnosis has been acknowledged only recently, and very slowly the perception is arising that not all cancers are lethal if untreated. Currently, it is being discussed that ‘cancer’ should be redefined [11–13]. Laurence Klotz [11] has offered a new appealing definition: ‘Cancer is simply a pathological description of tissue made at a single point of time, rather than a prediction about the natural history of a disease’. Impressive data exists on the natural history of prostate cancer that supports this definition: In a Swedish cohort of men with untreated, localized prostate cancer, only 17% died of their cancer after a follow-up of 32 years [14]. The idea of a new understanding of cancer is still reDecisions about Cancer Screening – Based on Beliefs or Facts? Corinna Schaefer Lothar Weißbach