[The importance of pathology in the German prostate cancer study PREFERE]. / Die Bedeutung der Pathologie in der deutschen Prostatakrebsstudie PREFERE.

Prostate cancer is the most common carcinoma of elderly males and holds the third place in the ranking of cancer-specific mortality. However, total mortality rate of 3 % is low and half of the patients die from other diseases, which is for the most part due to significantly improved diagnostic methods and the increasing use of prostate-specific antigen (PSA) screening. This has led to a stage migration towards early tumor stages that are prognostically heterogeneous and require differentiated treatment. The German and European guidelines recommend four therapy options (i.e. radical prostatectomy, percutaneous irradiation, permanent seed implantation and active surveillance) for localized prostate cancer and from contemporary study data it is unclear which therapy is most beneficial. This will be the subject of the PREFERE trial, a prospective randomized multicentre trial which plans to recruit 7,600 patients and to observe them over a period of up to 17 years. The histopathological diagnosis of the primary biopsy plays a crucial role in the inclusion criteria, as this article outlines in detail.

[PREFERE - the German prostatic cancer study: questions and claims surrounding study initiation in January 2013]. / PREFERE - die Deutsche Prostatakrebsstudie : Fragen und Behauptungen rund um den Studienbeginn im Januar 2013.

The PREFERE study is a multicenter randomized study of patients with low or early intermediate risk for prostatic cancer. The four treatment options, radical prostatectomy, percutaneous irradiation therapy, permanent seed implantation and active surveillance recommended by the German S3 guidelines and international guidelines will be tested and compared with respect to effectiveness and potential side effects. Over a period of 4 years a total of 7,600 patients are to be recruited and assigned to 1 of these 4 therapy forms according to personal preference (by possible exclusion of 1 or 2 therapy options) in a 2-4 arm study design by randomization.

[Clinical studies outside university clinics : What are the problems to implement this?]. / Klinische Studien ausserhalb von Universitätskliniken : Wo liegen Probleme bei der Durchführung?

The demand for high quality evidence-based surgical treatment in Germany and awareness of the poor quality of surgical trials highlight the basic necessity of randomized controlled trials. In six surgical trial centers a professional infrastructure for surgical trials is in the process of being established since 2006.The aim is the initiation of surgical multicenter trials which can be effectively conducted by local networking. To accomplish a timely recruitment of patients it is necessary to integrate surgical departments outside university hospitals into multicenter trials. With a questionnaire survey of non-university surgical departments in the federal states of Berlin and Brandenburg, interest, experience in clinical trials and structural conditions in these departments were evaluated. Based on the results of this survey the possibilities to integrate non-university surgical departments into multicenter trials and how a high recruitment of patients can be motivated will be discussed in this article.

RPLND or primary chemotherapy in clinical stage IIA/B nonseminomatous germ cell tumors? Results of a prospective multicenter trial including quality of life assessment.

BACKGROUND: In order to reduce therapy-related morbidity in patients with nonseminomatous testicular germ cell tumors in clinical stage IIA/B, we performed a prospective multicenter trial comparing the standard retroperitoneal lymph node dissection (RPLND) +2 cycles of chemotherapy (arm A) with 3-4 cycles of primary chemotherapy (arm B). METHODS: From February 1991 to July 1995, 57 participating centers from Germany and Austria recruited 187 evaluable patients. 109 received primary RPLND and 78 primary chemotherapy. Two different chemotherapies were applied (PEB and CEB as adjuvant or inductive treatment). The quality of life (QoL), therapy-related morbidity, suspected predictive factors (histology and size of metastases), and outcome were assessed. RESULTS: In arm A, 12% had pathological stage (PS) I, 70% PS II A/B, and 18% PS II C/III. In arm B, 67% achieved complete remission with chemotherapy alone, 33% required a secondary RPLND. After a median follow-up of 36 months, 7% of the patients in arm A and 11% in arm B had relapsed. Two patients died due to complications of chemotherapy. Surgical complications amounted to 12% in arm A and 27% of 26 postchemotherapy RPLNDs (9% in arm B). Loss of ejaculation occurred in 32% in arm A, and 16% in arm B. Acute toxicity of chemotherapy was higher in the group receiving primary chemotherapy. CONCLUSION: We recommend primary RPLND because adjuvant chemotherapy can be spared in PS I, two cycles of chemotherapy are less toxic than 3 or 4 cycles, the primary operation is associated with less complications than that following chemotherapy and, with modern surgical procedures, ejaculation can be preserved in most of the patients, provided that the operation is carried out by an experienced surgeon. No statistically significant differences in the QoL outcome occurred between the treatment groups, suggesting that chemotherapy alone is not superior to primary or secondary RPLND in this respect.

Second malignancies following pure seminoma.

PURPOSE: Second malignancies in patients with pure testicular seminoma were studied in order to look for adverse late effects of treatment and to study the significance of second malignancies during follow-up. PATIENTS, METHODS: In a multicentric investigation, 839 consecutive patients with pure testicular seminoma were observed for a median follow-up of 3.9 years. Thirty-seven patients had been excluded from the study because they already had had either a contralateral testicular germ cell tumor or another malignancy. 758 patients received radiotherapy, 76 underwent chemotherapy, 5 had surveillance only. The expected rate of second cancers was calculated according to the data of the cancer registry of Saarland, Germany. RESULTS: Twenty-two second cancers (13 contralateral testicular tumors, 9 extratesticular malignancies) were recorded. The overall risk of having a second cancer was RR = 4.8 (95% CI 3. 0-7.3). The risk of having a subsequent testicular tumor is RR = 44. 8 (95% Cl 23.9-76.7). 1.1% of the patients developed a nontesticular second tumor. The risk of having a nontesticular second cancer is RR = 2.1 (95% CI 1.0-4.0). A significantly increased risk was observed for renal cell cancer as well (RR = 12.5; 95% Cl: 1.5-45.1). Increased RR without reaching statistical significance were found for rectal cancer (RR = 5.0; 95% Cl: 0.1-27.9) and non-Hodgkin lymphoma (RR = 6.7; 95% CI 0.2-37.1). None of the second cancers were directly located within the radiation field; 5 neoplasms arose at the border of the radiation field. CONCLUSIONS: This study confirmed the increased risk of having a second testicular germ cell cancer. There is also a small but definitely increased overall risk of having a nontesticular second cancer. Treatment-unrelated factors - possibly genetic predisposition - must be considered for a substantial number of these second tumors, since in the present study the follow-up was rather short and most of the second cancers were located outside of the radiation fields. In particular, the association of renal cancer with testicular cancer appears to be a more than chance occurrence. Second cancer is a real hazard following treatment of testicular cancers and should always be considered during follow-up.

Prognostic factors in seminomas with special respect to HCG: results of a prospective multicenter study. Seminoma Study Group.

OBJECTIVE: In a prospective multicenter trial, it was our intention to elucidate clinical prognostic factors of seminomas with special reference to the importance of human chorionic gonadotropin (HCG) elevations in histologically pure seminomas. METHODS: Together with 96 participating urological departments in Germany, Austria, and Switzerland, we recruited 803 seminoma patients between 1986 and 1991. Out of 726 evaluable cases, 378 had elevated, while 348 had normal HCG values in the cubital vein. Histology was reviewed by two reference pathologists. HCG levels were determined in local laboratories and in a study laboratory. Standard therapy was defined as radiotherapy in stages I (30 Gy) and IIA/B (36 Gy) to the paraaortal and the ispilateral (stage I) and bilateral (stage IIA/B) iliac lymph nodes; higher stages received polychemotherapy and surgery in case of residual tumor masses. Statistics included chi-square tests, linear Cox regression, and log-rank test. RESULTS: The HCG elevation is associated with a larger tumor mass (primary tumor and/or metastases). HCG-positive and HCG-negative seminomas had no different prognostic outcome after standard therapy. The overall relapse rate of 6% and the survival rate of 98% after 36 months (median) indicate an excellent prognosis. The calculation of the relative risk of developing a relapse discovered only stage of the disease and elevation of the lactate dehydrogenase concentration and its prolonged marker decay as independent prognostic factors for seminomas. A more detailed analysis of the prognostic significance of the stage revealed that the high relapse rate in stage IIB seminomas after radiotherapy (24%) is responsible for this result. CONCLUSIONS: We conclude that HCG-positive seminomas do not represent a special entity. Provided standard therapy is applied, HCG has no influence on the prognosis. Patients with stage IIB disease should be treated with chemotherapy because of the demonstrated higher relapse rate outside the retroperitoneum.

The value of tumor markers in testicular seminomas. Results of a prospective multicenter study.

OBJECTIVES: In the course of a prospective multicenter trial, the value of tumor markers in seminomas was assessed. METHODS: Human chorionic gonadotropin (HCG), lactate dehydrogenase (LDH) and placental alkaline phosphatase (PlAP) were determined before and after orchidectomy and in the follow-up. Patients with elevated alpha-fetoprotein were considered to have nonseminomas. The half-lives were 24-36 h for HCG and 1 day for LDH and PlAP. RESULTS: The incidence of HCG, LDH and PlAP was 35, 34 and 56%, respectively. In 84% of the patients at least one of the three markers was elevated. PlAP had the highest sensitivity to detect metastatic disease (51%), with a specificity of 91%. HCG and LDH were elevated in 42 and 46% of patients in stage II-III with specificities of 95 and 96%. PlAP was the best method to indicate a relapse, but the specificity was low, especially in smokers. For nonsmokers it was in the same range as HCG and LDH. CONCLUSIONS: Eighty-four percent of seminomas are marker-positive. PlAP has the highest incidence and sensitivity. Specificity is impaired in smokers. All three markers should be determined in seminomas.

Elevated human chorionic gonadotropin concentrations in the testicular vein and in peripheral venous blood in seminoma patients. An analysis of various parameters.

OBJECTIVE: Human chorionic gonadotropin (HCG) elevations in the testicular vein (TV) are correlated with those in the cubital vein (CV). Their significance was tested regarding various prognostic parameters. METHOD: Within the framework of a large multicentre study to assess the prognosis of HCG-positive seminomas 726 eligible patients were recruited from 1986 to 1991. A total of 378 had elevated and 348 had normal HCG measured in the CV. In 144 patients samples were taken from the TV. Histological diagnosis of seminoma was confirmed by two reference pathologists. Three groups (group I: elevated HCG in CV and normal or elevated HCG in TV; group II: normal HCG in CV and elevated HCG in TV; group III: normal HCG in CV and normal or unknown HCG in TV) were compared in relation to the presence or absence of metastases, stage of the disease, size of the primary tumour, pT category, vascular invasion and lactate dehydrogenase. RESULTS: Of the TV serum samples, 85% were HCG-positive. Regression analysis revealed higher values in the TV compared to the CV according to the following equation: HCGTV = 520 + 1.12 x HCGCV, R = 0.766, with a mean variation of 14%. Patients in group I had significantly higher stages and larger primary tumours than patients with normal HCG in the CV, irrespective of the HCG values in the TV blood (groups II and III). Therefore, HCG is associated with tumour mass. No differences of statistical significance were found regarding T category, vascular invasion and lactate dehydrogenase. There were no differences between groups II and III. CONCLUSION: Only HCG values of the CV are associated with known adverse-prognostic factors of seminomas, such as metastases and size of the tumour. HCG in the TV adds no further information for the clinical assessment of patients with seminoma.

Size and status of metastases after inductive chemotherapy of germ-cell tumors. Indication for salvage operation.

Secondary resection of metastases remaining after inductive chemotherapy of advanced germ-cell tumors has thus far been obligatory. The absence of malignant components in one-third of all residual tumors and the high risk of the operation have led several authors to reconsider the criteria for this approach. In a retrospective study of 153 cases (127 evaluable) we investigated the histology of the primary tumor and the size of the residual tumor with regard to residual histology and outcome. Patients were divided into the following three groups according to the histology of the primary tumor: group I, pure seminoma (16 patients); group II, nonseminoma without teratoma (32 patients); and group III, nonseminoma with teratoma (79 patients). Among the 16 purely seminomatous tumors, the residual masses ranged from 2 to 12 cm; 12 consisted of necrotic tissue only, 3 contained malignant germ-cell elements, and 1 contained adult teratoma. The residuals of primarily teratoma-free nonseminomas measured 2-16 cm; the smallest residual tumor containing active malignant elements measured 4 cm, and the diameter of the largest necrotic residue was 6 cm. Four residuals contained mature teratoma. The size of residuals from teratomatous primary tumors was 3-24 cm; the smallest malignant tumor measured 5 cm, and the diameter of the largest purely necrotic mass was 8 cm. According to our results, a secondary operation may be omitted if the residual mass of a primary seminoma is smaller than 5 cm or if that of a primary nonseminoma without teratoma is less than 3 cm in diameter.(ABSTRACT TRUNCATED AT 250 WORDS)

Deoxyribonucleic acid ploidy in seminomas with and without syncytiotrophoblastic cells.

Seminomas with human chorionic gonadotropin-producing syncytiotrophoblastic cells have been discussed as a distinctive subgroup with a worse prognosis. In a series of 50 seminomas (30 with immunohistochemically detectable syncytiotrophoblastic cells and 20 without syncytiotrophoblastic cells) deoxyribonucleic acid (DNA) ploidy was determined by flow cytometry in paraffin-embedded histopathological material. Comparatively, in 28 cases the DNA content was assessed by image cytometry on Feulgen-stained slides. DNA aneuploidy was detected in 49 seminomas (98%). No differences in the distribution of DNA index were observed between cases positive and negative for syncytiotrophoblastic cells (average DNA index 1.68 +/- 0.44 for positive cases and 1.71 +/- 0.52 for negative cases). Flow cytometry and image cytometry DNA index values showed a statistically significant correlation (p < 0.01). Intra-tumoral heterogeneity of DNA content was found in 2 seminomas negative for syncytiotrophoblastic cells. Multiploidy and hypertetraploidy were noted more often in negative cases also. DNA ploidy or distinct aneuploid stemlines did not correlate with histopathological tumor stage or clinical course. The results favor the notion that the occurrence of syncytiotrophoblastic cells in seminomas represents only an example of intra-tumoral variability of tumor cell differentiation and does not justify the definition as a separate subgroup with distinct biological behavior.

Retroperitoneal lymph node staging of testicular tumours. TNM Study Group.

A prospective multicentre study was carried out to determine the efficiency of various diagnostic methods in the assessment of the retroperitoneal space. The diagnostic findings were confirmed histologically after retroperitoneal lymph node dissection (RLND). The sensitivity was 71% for bipedal lymphography, 41% for computed tomography (CT), 31% for abdominal ultrasound and 37% for alpha-fetoprotein/human chorionic gonadotrophin (AFP/HCG). Specificity was 60, 94, 87 and 93% respectively. When all diagnostic methods were combined, sensitivity was 88% and specificity 48%. The value of all methods depends on the metastatic enlargement of the lymph nodes. The predictive value of a negative diagnosis was 73% for lymphography, 67% for CT, 61% for ultrasound and 65% for AFP/HCG; the predictive value of a positive diagnosis was 58, 85, 69 and 81% respectively. Despite these results, lymphography is indicated only when a surveillance strategy is planned, since it detected 58% of the lymph node metastases that were overlooked by CT and tumour markers. Despite this, 17% of patients with clinical stage I tumours had metastases. False positive rates are detrimental to primary chemotherapy: between 24% (at least 2 methods positive) and 46% (1 or more methods positive) of patients with clinical stage II A/B tumours had a pathological stage I and for these patients primary chemotherapy meant overtreatment.

[The "false positive" tumor marker in malignant testicular tumor]. / Der "falsch-positive"Tumormarker beim malignen Hodentumor.

In addition to the histological diagnosis, alpha fetoprotein (AFP) and chorion gonadotropin (HCG) are used in clinical staging, therapy monitoring, and follow-up. Elevated markers without localization of metastases by imaging procedures are generally classified as progressive disease. However, other causes may be responsible for the elevated tumor markers: other malignant or benign diseases such as hepatocellular carcinomas, gastrointestinal tumors, bronchial carcinomas and benign diseases of the liver for AFP, and vesicular mole, hepatocellular, stomach, pancreatic and urothelial carcinomas for HCG. Moreover, technical disturbances in the modern sandwich assays with monoclonal antibodies are possible by heterophilic antibodies. These human anti-animal antibodies are built after immunoscintigraphy, immunostimulation and oral immunization by macromolecules. As a result, if progressive disease of a malignant germ cell tumor is unlikely, several steps have to be taken to determine the true causes for the elevated tumor markers before chemotherapy can be applied.

[Therapy of non-seminomatous testicular tumor stage II A/B (pT+N1/2Mo)]. / Therapie des nichtseminomatösen Hodentumors in Stadium II A/B (pT+N1/2Mo).

In these stages standard therapy (RLND + 2 courses PEB) reveals survival rates of more than 95%. The high rates of toxic side effects from two aggressive treatment strategies induce considerations about reducing therapy. We may be able to omit one of the therapeutic methods: (a) RLND alone can cure half of the patients; the others could have chemotherapy if progression is found. (b) Primary chemotherapy shows complete remission in 75% of the cases; only every fourth patient has to undergo surgical resection of a residual tumor. Survival rates for both strategies are no different than those following standard therapy. Further modifications concern surgical techniques (modified unilateral RLND, nerve sparing RLND) in order to preserve an antegrade ejaculation, as well as other chemotherapy regimens by omitting one of the drugs (PE instead of PEB) or replacing one by another with fewer toxic effects (CEB instead of PEB). Current clinical trials should answer the question of which of the therapeutic options impairs quality of life less.