[Strategies for First-Line Treatment of mCRPC]. / Strategien für die Erstlinientherapie des mCRPC.

At present, abiraterone acetate and enzalutamide are the most commonly used substances in the first-line treatment of asymptomatic or mildly symptomatic metastatic castration-resistant prostate carcinoma (mCRPC). Since the relevant pivotal trials have demonstrated comparable clinical efficacy for both substances, further factors should be considered for the choice of treatment. As mCRPC patients usually receive several lines of treatment, different adaptation and resistance mechanisms leading to treatment failure could be important. This is indicated by daily routine observations and some initial clinical studies on resistance and different sequences of therapy. However, until the clinical relevance has been confirmed, it is mostly adverse events and comorbidities that are taken into account for the choice of first-line therapy. Also potential interactions with comedications and patient preferences should be considered. In the first-line treatment of mCRPC, ongoing discussions not only centre around the choice of medication for first-line mCRPC therapy, but also around the point in time they are started. For abiraterone acetate, for example, there is confirmed evidence that patients may benefit from early use within the approved indication. If the clinical importance of the different resistance mechanisms and differences in efficacy of various sequences could be confirmed, this would be a strong argument for therapy decisions and should therefore be further analysed in prospective clinical studies.

[Mechanisms of Resistance in Antihormone Therapies of Advanced Prostate Cancer]. / Resistenzmechanismen unter antihormoneller Therapie des fortgeschrittenen Prostatakarzinoms.

With the development of Abiraterone and Enzalutamide new treatment option have become available in addition to Docetaxel for first-line treatment of castration resistant prostate cancer. However, resistance and ultimately failure occurs inevitably with all available treatment options. Moreover, cross-resistance leads to considerably reduced efficacy in second-line treatment. Preclinical data suggest discriminative mechanisms of resistance development for Abiraterone and Enzalutamide. Clinical confirmation of these putative mechanisms for treatment failure might facilitate recommendations for future sequencing of these drugs.

[Testosterone in the management of metastatic prostate cancer]. / Testosteron im Management des metastasierten Prostatakarzinoms.

Background Among all cancer types, prostate cancer (PCa) is the most prevalent cancer and is the third-leading cause of cancer-related death in men. The biologic function of the prostate is decisively influenced by testosterone and its metabolic product dihydrotestosterone. However, there is general uncertainty about the role of testosterone in metastatic castration-resistant prostate cancer (mCRPC). For many years, the androgen hypothesis had been accepted to explain the correlation between testosterone levels and the development or progression of PCa. However, extensive study analyses revealed contradictory results, leading to a reconsideration of the androgen hypothesis. High serum testosterone levels do not predispose to PCa development and low serum testosterone levels are not protective. The importance of testosterone levels in patients with mCRPC has been shown in several registration studies with new drugs, such as abiraterone acetate and enzalutamide. There is growing evidence suggesting a prognostic role of testosterone levels in mCRPC.

[Value of intermittent androgen deprivation in the context of the current data situation]. / Stellenwert der intermittierenden Androgendeprivation im Kontext der aktuellen Datenlage.

Androgen deprivation therapy is an integral part of the treatment of advanced and progressive prostate cancer. Various prospective randomised trials have investigated whether or not temporary suspension of androgen deprivation might delay the emergence of castration resistant prostate cancer and concomitantly improve quality of life. Until now, no phase III trial has been able to prove that intermittent androgen deprivation might delay the development of castration resistant tumours. Data from previous trials, except for one study, did at least not show adverse effects on survival. Data on quality of life are inconsistent, showing a trend towards improved quality of life with IAD. German as well as European guidelines reflect IAD as an established constituent of day-to-day medical practice. This review is intended to provide a code of practice for an individualised treatment as based on recently published studies.

[Pathophysiology and therapy of castration-resistant prostate cancer]. / Pathophysiologie und Androgendeprivationstherapie des kastrationsresistenten Prostatakarzinoms.

Advanced prostate cancer that progresses under androgen deprivation therapy has long been thought to be refractory to further hormonal treatment. The identification of the mechanism of cancer cells has revolutionized this understanding. Today it is known that castration-resistant prostate cancer (CRPC) still receives signals through the androgen receptor transduction pathways and furthermore is sensitive to hormone therapy. New substances, such as abiraterone, enzalutamide (MDV3100) and TAK 700 target these mechanisms of resistance of cancer cells, stop testosterone production and show not only better tolerance but also effective antitumor activity. Due to the heterogeneity of tumors with cells in varying states of differentiation, the treatment of CRPC with androgen deprivation therapy remains a cornerstone of disease management. To what extent the experimental findings and the recommendations in the guidelines are put into practice was the subject of a survey among urologists analyzing their treatment strategies with CRPC patients.

Drivers for change in the management of prostate cancer - guidelines and new treatment techniques.

Clinical practice guidelines and new treatment techniques are of particular importance for the effective management of prostate cancer. In Europe, the European Association of Urology guidelines offer a regularly updated evidence-based source of recommendations for the optimal treatment of prostate cancer. This review examines recent changes to guidelines highlighting developments in diagnosis, hormonal therapy in advanced and metastatic disease, bone protection, the definition of new terminology such as castrate-resistant prostate cancer, treatment of relapse after hormonal therapy, and cytotoxic therapy for castrate-resistant prostate cancer. The review also examines new surgical and radiotherapeutic developments in prostate cancer. This includes minimally invasive techniques such as robot-assisted radical prostatectomy, which is becoming the surgical gold standard for clinically localized disease in many countries. Other promising techniques reviewed include cryosurgical ablation of the prostate, laser-induced interstitial thermotherapy, vascular-targeted photodynamic therapy, and high-intensity focused ultrasound; with the exception of cryotherapy, these approaches are not currently recommended for routine clinical use. Finally, we will review the evidence supporting intensity modulated radiotherapy, an optimized high-precision form of three-dimensional conformal radiotherapy which aims to allow homogeneously increased radiation doses, without increased toxicity to healthy at-risk organs. Novel techniques such as proton beam or carbon ion radiotherapy, which may offer improved and more localized dose distribution with reduced damage to normal tissue, are also examined.

[Intermittent androgen deprivation in advanced prostate cancer: a review]. / Die intermittierende Androgenblockade beim fortgeschrittenen Prostatakarzinom - eine Übersicht.

At present androgen ablation therapy is the therapy of choice for the treatment of metastatic prostate cancer. However, in more than 50 % of the patients the disease will ultimately progress within 2 years.On the basis of the postulation from Bruchovsky et al. that intermittent androgen deprivation maintains the apoptotic potential, this may lead to a delay in tumour progression. By periodically changing phases from on to off the treatment quality of life for the patient may be improved. Most recent clinical data of phase II and III studies imply that IAB is equal effective as CAB. Although data about quality of life and overall survival are still limited, results seem to be comparable. In order to decide which patient groups are most likely to benefit from IAB, final phase III results need to be available.

[Systemic treatment of metastatic prostate cancer]. / Die systemische Therapie des metastasierten Prostatakarzinoms.

Systemic treatment of advanced prostate cancer is multifaceted. First-line therapy is antihormonal treatment with androgen deprivation or antiandrogens. Chemotherapy is effective in hormone refractory (castration resistant) prostate cancer. Alternative and supplementary options include radionuclides, steroids, and symptomatic measures. Use of bisphosphonates is standard in metastatic bone disease. Treatment of patients with metastatic prostate cancer is palliative. The aims are prolongation of overall survival, prolongation of progression-free survival, control and relief of symptoms, and restoration and maintenance of quality of life. Current options allow personalized patient care. New approaches and new drugs will increase the therapeutic possibilities considerably.

[GnRH antagonists--a new therapy option for advanced prostate cancer]. / GnRH-Antagonisten - eine neue Therapieoption beim fortgeschrittenen Prostatakarzinom.

At present medical castration employing luteinising hormone releasing hormone (LHRH) agonists is the standard of care for patients with advanced prostate cancer. LHRH agonists suppress the synthesis of testosterone to a castration level. In contrast to surgical castration, medical castration is reversible. However LHRH agonists induce an initial increase of the testosterone level. This so-called testosterone surge leads to tumour growth and increases the disease-specific complaints, known as flare phenomena. It may be possible that the overall survival of these patients is deteriorated. In contrast, gonadotrophin releasing hormone (GnRH) antagonists do not induce a testosterone surge and the level of testosterone decreases as rapidly as that known from a surgical castration.

[Adjuvant hormone therapy for prostate cancer after local treatment in the context of evidence based medicine]. / Die adjuvante Hormontherapie des Prostatakarzinoms nach lokaler Therapie im Kontext der evidenzbasierten Medizin.

At present, prostate cancer is the most frequent malignant disease in German men. The aims of adjuvant hormone treatment are to increase progression free survival and improve cure rate. Risk factors for progression are a Gleason score > or =8, large tumor volumes, a high preoperative PSA (>15-29 ng/ml), penetration of the capsule, positive margins and lymph node metastasis. The type of hormone therapy (LHRH-nnalogues, non-steroidal anti-androgens, surgical castration) should be discussed with the patient. Bicalutamide seems to be an alternative for younger patients due to the lack of side effects of testosterone suppression.

[Interdisciplinary recommendations concerning the therapy for hormone-refractory prostatic carcinoma]. / Interdisziplinäre Therapieempfehlungen zur Behandlung des hormonrefraktären Prostatakarzinoms.

Therapy with Docetaxel for hormone-refractory prostatic carcinoma has for the first time led to an increase in the survival time. Docetaxel has become established as a standard therapy for his indication. Since hormone-refractory prostatic carcinoma is not uniformly defined and is thus for prognosis not a homogeneous entity, the prospects at the start of chemotherapy are uncertain. In the summer of 2005 these questions were addressed in an interdisciplinary consensus conference. It was agreed that the 3-week scheme with 75 mg/m (2) as standard and the indication for symptomatic patients were above question. Opinions differed with regard to the use of chemotherapy in asymptomatic patients. In addition, recommendations for the performance and monitoring of the therapy were formulated.

[The role of PSA in diagnosis of prostate cancer and its recurrence]. / Stellenwert des prostataspezifischen Antigens (PSA) in der Primär- und Rezidivdiagnostik des Prostatakarzinoms.

Prostate specific antigen is the most important tumor marker of prostate cancer. PSA, in conjunction with digital rectal examination, is the first-line clinical tool for detection of prostate cancer. To improve its specificity PSA-density, PSA-ratio (fPSA/tPSA), PSA-velocity, and complexed PSA have been introduced into clinical praxis. The treatment of lower stage disease in younger men has resulted in a longer period of post-treatment cancer surveillance. Biochemical recurrence is an early indicator for clinical disease recurrence. PSA doubling time allows to distinguish between local and systemic progression and is also a valid predictor for distant metastasis and death of disease.

Intermittent androgen castration: a biological reality during intermittent treatment in metastatic prostate cancer?

INTRODUCTION: To assess the effects of intermittent maximal androgen blockade (IMAB) on testosterone (T) levels during on- and off-treatment periods. MATERIALS AND METHODS: A total of 51 patients with metastatic prostate cancer underwent a 6-months period of continuous maximal androgen blockade (MAB) consisting of leuprorelin (3.75 mg at monthly intervals) plus flutamide (250 mg t.i.d.) followed by IMAB. During each cycle, the cut-off prostate-specific antigen (PSA) levels to stop and resume treatment were 4 and 10 ng/ml, respectively. IMAB continued until progression under treatment occurred. Monthly PSA and T measurements were performed in central laboratories. RESULTS: From the 51 patients included (mean age 67.6 years), 27, 16, 12, 8 and 5 underwent a second, third, fourth, fifth and sixth cycle, respectively (mean follow up: 17 months). Before treatment, 4 patients had a T lower than normal laboratory value but these recovered all to a normal T value at the end of the first cycle. During the 6 cycles, only 8 patients did not recover a normal T at least once during the off-treatment periods (OTP). The mean T values at the end of each OTP did not change during these 6 cycles (Anova test, p=0.621) with a mean stable recovery delay of 32-43 days (Anova test, p=0.722). CONCLUSION: IMAB protocol with an initial 6-month treatment period can result in an intermittent castration with the recovery of normal T levels in most patients during six consecutive cycles of treatment.

[The aftercare principle for metastasizing prostate cancer. Few diagnostics, much support]. / Das Nachsorgeprinzip beim metastasierten Prostatakarzinom - Wenig Diagnostik, viel Support.

For advanced prostate cancer - not including intermittent strategies - the patient is in continual treatment. The effect of the therapy must be controlled so that its failure can be determined as soon as possible and a new regimen started. As in most cases the progression of the disease can not be stopped, the aim of the therapy is to provide the patient with the best possible quality of life. In order to carry out therapy, if possible in the patient's usual environment, supportive therapies should be used, such as compensation for anaemia or pain therapy as required. Skeletal complications can be prophylactically treated by the use of biphosphonates.

[Urological illnesses in the elderly]. / Urologische Erkrankungen im Alter.

Urological illnesses in the elderly are a growing clinical problem because as life expectancy increases so does the prevalence of such illnesses. However, sufficient data for judging the various possible therapies are lacking for patients over the age of 70. Age itself does not have enough predictive value for the determination of the best treatment. It seems more important to estimate the functional and socio-economic status, comorbidity, and the cognitive and emotional abilities of elderly patients as well as their nutritional intake.

[Chemotherapy of the hormone-refractory prostate cancer]. / Chemotherapie des hormonrefraktären Prostatakarzinoms.

The scepticism dominating the chemotherapy of the hormone-refractory prostate cancer (HRPC) has been replaced by a wave of enthusiasm. Phase II studies with taxane-containing combination therapies could achieve high response rate in some cases, and HRPC can not longer be deemed resistant to chemotherapy. It remains to be seen whether the combinations offer a survival advantage. This will be tested in phase III studies. Palliative chemotherapy should be considered in patients with HRPC if the initial hormone therapy was effective for a short time only and after several hormone therapies have been completed. Since chemotherapy is not yet an established standard therapy of HRPC, patients should be, if possible, included in clinical studies.

[Significance of docetaxel in the chemotherapy of hormone-refractory prostate cancer]. / Bedeutung von Docetaxel für die Chemotherapie des hormonrefraktären Prostatakarzinoms.

Docetaxel (Taxotere) is a taxoid derived from the European yew tree, taxus baccata. In 4 phase-II studies docetaxel has important single agent activity with an overall prostate-specific antigen response rate of 42% in hormone refractory prostate cancer. Other phase-II studies suggest that the addition of estramustine to docetaxel results in a higher response rate but also in an increased toxicity. At present Docetaxel with and without estramustine is being evaluated in phase-III studies that will provide definitive information about its role in hormone refractory prostate cancer.