Prostate cancer (PC) is the most commonly diagnosed malignant tumour in men today resulting in a major public health oncology problem in developed countries. In Germany more than 67.000 new cases are predicted to be diagnosed in 2012. PC is accounting for approximately 15% of all cancer related deaths and about 12.200 men die annually due to PC.

Prostate cancer itself represents a very heterogenous disease with the majority of patients being diagnosed with low risk PCA and about 20-25% of patients being diagnosed with high risk disease at time of diagnosis. The standard treatment for patients with high risk prostate cancer is radical prostatectomy with extended pelvic lymphadenectomy or external beam radiation with adjuvant androgen deprivation therapy for 3 years. However, the group of high risk patients is very heterogenous: about 20-25% of the patients are overstaged and harbour organ confined lymph node negative PCA and will be cured by surgery alone. The remainder has more or less extensive disease depending on the presence of one, two or three of the above mentioned risk factors.

According to the D’Amico classification patients with a PSA > 20 ng/ml, biopsy Gleason score 8-10 or clinical stage ≥ cT3a are considered high risk PCA. This definition is used in various guidelines including the EAU guidelines on the diagnosis and management of PC. The difficulty comes in the risk evaluation of so-called ‘high-risk’ disease where there is confusion between anatomical considerations and pathological/biological parameters resulting in localized versus locally advanced disease classifications and an unclear disease spectrum. Patients with high-risk prostate cancer comprise a heterogeneous group of those with a high T-stage and those with a lower T-stage, but adverse features such as a high PSA level or Gleason score. Distinguishing patients with a poor prognosis from those with a favourable prognosis is a challenge for physicians, particularly as the definition of the ’risk’ differs between specialities. Surgeons often evaluate the 75 risk of positive margins or extracapsular invasion to decide which patients should receive surgery, including nerve-sparing surgery. For radiation oncologists, the issues revolve around the use, setting and duration of hormone therapy, as the extent of local-regional disease may be anticipated by predictive tools. Surgeons and radiation oncologists assess the risk of lymph-node positivity and PSA recurrence to determine the extent of surgery or irradiation and to advise on adjuvant irradiation and/or androgen-deprivation therapy (ADT). However, extracapsular extension and positive margins are surrogates for biochemical failure, and biochemical failure is not a true surrogate for overall survival. Indeed, in radiotherapy dose-escalation trials, a PSA relapse-free survival advantage has not been transformed into improvements in overall or metastasis-free survival. Therefore, the relative risk of death from cancer versus that from other causes, and the risk–benefit of treatment versus toxicity should drive therapeutic decisions. As an illustration, if therapeutic decisions are driven by an improvement in PSA progression-free survival, then all men with an extracapsular extension, positive margin or seminal vesicle invasion at RP should receive adjuvant irradiation. However, the therapeutic decision is less clear cut if driven by lowering the mortality risk. Furthermore, when evaluating the risk of dying, prostate cancer-related mortality should be separated from all-cause mortality. Interestingly, most current risk stratification tools address only tumour characteristics and rarely include patient characteristics such as comorbidities. Improving the characterization of patients with high-risk prostate cancer (i.e. those  with a high risk of prostate cancer-specific mortality) should allow physicians to plan treatment strategies for their patients proactively at presentation, matching treatment intensity to disease aggressiveness and expected prognosis. Bastian et al. have recently reviewed the treatment options for patients 100 with high-risk prostate cancer. Acknowledging the lack of randomized controlled trials comparing different treatment modalities, they suggested multimodal management as the optimal approach in most cases of high-risk prostate cancer. Given the variability in high-risk prostate cancer definitions across guidelines and clinical trials, a refined definition will improve patient management by ensuring a multidisciplinary and multimodal approach to patient management. It will also help standardize high-risk prostate cancer cohorts across clinical trials to allow better and more meaningful comparisons between trials.

Most recently, Spahn et al. have evaluated the outcome of 550 high risk patients who underwent radical prostatectomy, extended pelvic lymphadenectomy and adjuvant androgen deprivation or adjuvant radiation therapy. Overall 173 of 550 patients (31.5%) with a median followup of 67 months met the study inclusion criteria. For these men the estimated 8-year prostate cancer specific and overall survival rates were 86.3% and 77.0%, respectively. Tumor stage and positive surgical margin at the bladder neck were independent predictors of prostate cancer specific survival and overall survival, and were used to substratify cases. Those with pT3b disease with positive surgical margins at the bladder neck had the highest risk of death (5-year cancer specific survival 60.0% and overall survival 52.3%), while pT3a disease (regardless of positive surgical margin location and lymph node invasion) and pT3b tumors with negative bladder neck margins had 8-year prostate cancer specific survival and overall survival rates of 92.0% and 84.9%, respectively. Similarily, Joniau et al. of 51 very high risk prostate cancer patients (defined as cT3b-cT4 PC) after a median follow-up of 108 months. The biochemical progression-free survival, clinical progression-free survival, cancer specific survival and overall survival at 5 and 10 years were 52.7%, 45.8%;78.0%, 72.5%; 91.9%, 91.9% and 88.0%, 70.7%. In the multivariate Cox proportional hazard models, pathological stage was an independent predictor of BPFS while preoperative PSA and pathological Gleason Score was an independent predictor of CPFS.

To harmonize a group of high risk patients the Kattan nomogram has been shown to represent the most reliable nomogram to predict the 5-years disease free probability. The nomogram has been internally and externally validated in cohort of US American, European and African patients. The probability of disease recurrence can be easily calculated by the use of the clinical stage, the primary and secondary biopsy Gleason grade, and the preoperative PSA serum concentration. High risk patients are defined as those patients who have a 5-year relapse probability ≥ 60%.

The outcome of these patients usually is poor with a 10 year biochemical free survival rate of only 17% and a metastasis free survival rate of only 32%. Also, adjuvant treatment with androgen deprivation therapy has not demonstrated a significant overall and cancer specific survival benefit. The most probable reason for the poor response is the presence of systemic and locoregional castration resistant PCA clones already at time of diagnosis as has been demonstrated by Tzelepi et al who treated 40 patients with locally advanced prostate cancer by neoadjuvant chemohormonal therapy followed by radical prostatectomy. 30 (75%) patients underwent prostatectomy and two (5%) who underwent cystoprostatectomy. Twenty-nine specimens contained sufficient residual tumor for inclusion in a tissue microarray. Immunohistochemical analysis showed increased epithelial and stromal expression of CYP17, SRD5A1, and Hedgehog pathway components, and modulations of the insulin-like growth factor I pathway. A network of molecular pathways reportedly linked to prostate cancer progression is activated after 1 year of therapy; biomarker expression suggests that potentially lethal cancers persist in the primary tumor and may contribute to progression.

Based on this hypothesis, very few clinical phase-II trials on adjuvant chemotherapy with docetaxel have been performed after radical prostatectomy. Kibel et al. analyzed the outcome of 77 patients with high risk PCA who underwent adjuvant docetaxel therapy with 6 cycles at 35 mg/m2 6 to 12 weeks after surgery. After a mean follow-up of 29 months, 60.5% of the patients progressed with a mean progression-free survival time of 15.7 months. Treatment was well tolerated but not therapeutically effective. In another study 17 patients with high risk PCA were treated with a combination of paclitaxel (90 mg/m2, 4 cycles, 21-day interval) and estramustine phosphate orally at a dose of 140 mg tid (Cetnar CP et al., 2008). The median calculated risk of 2-year PSA failure was 70%, but only 30% developed a PSA relapse (p < 0.01). The median time to PSA relapse was 19 months.

Neoadjuvant chemotherapy with docetaxel has been performed in various clinical phase-II trials. Konetty et al. have demonstrated the feasibility of RP following neoadjuvant chemo-hormonal therapy with 4 cyles of paclitaxel and carboplatin in a cohort of 36 high risk PCA patients. After a median follow-up of 29 months, 45% of all patients remained relapse free.

In another trial, Febbo et al. administered docetaxel for 6 months in 19 high risk PCA patients. 58% demonstrated a PSA decrease > 50% and 38% exhibited organ confined, lymph node negative disease after radical prostatectomy which could be performed without any complications. Dreicer et al. administered 6 cycles of docetaxel (40mg/m2) at weekly intervals followed by RP to 28 high risk PCA patients. They observed a significant decrease of the preoperative PSA value from 12 ng/ml to 8.4 ng/ml, and 93% of the patients achieved undetectable PSA levels postoperatively. After a median follow-up of 23 months, 20 (71.4%) patients remained without evidence of disease. Prayer-Galetti et al. reported the outcome of neoadjuvant chemohormonal therapy in 22 high risk patients after a median follow-up of 53 months. All PSA values decreased by > 90% in all patients and 3 patients had a complete remission, eight patients (42%) were disease-free. Organ-confined disease (P = 0.022), residual cancer at pathology in < or =10% of the surgical specimen (P = 0.007) and no seminal vesicle invasion (P = 0.001) correlated with disease-free survival.

Quite recently, Ross et al. have performed a clinical phase II trial of neoadjuvant docetaxel and bevacizumab in 41 men with high risk prostatectomy. Baseline characteristics included: median PSA, 10.1 ng/mL; cT2, 49%, cT3, 32%; and Gleason score 8 to 10, 73%. Thirty-eight of 41 (93%) patients completed all 6 cycles. Grade ≥3 adverse events were rare, although 3 of 41 (7%) experienced febrile neutropenia. Twelve patients (29%; 95% confidence interval [CI], 16%-45%) achieved a >50% reduction in tumor volume, and 9 patients (22%; 95% CI, 11%-38%) achieved a >50% post-treatment decline in PSA. Thirty-seven of the 41 patients underwent radical prostatectomy; there were no complete pathologic responses.

Narita et al performed another prospective trial of neoadjuvant chemohormonal therapy in 18 high risk PC patients. Complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m2) with estramustine phosphate (560 mg) were given before radical prostatectomy.  No patients had severe adverse events during chemohormonal therapy, and hence they were treated with radical prostatectomy. Two patients (11.1%) achieved pathological complete response. Surgical margins were negative in all patients. At a median follow-up of 18 months, 14 patients (77.8%) were disease-free without PSA recurrence. All 4 patients with PSA recurrence had pathologic T3b or T4 disease and 3 of these 4 patients had pathologic N1 disease. Neoadjuvant chemohormonal therapy with complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy was safe, feasible, and associated with favorable pathological outcomes in patients with a high risk of localized PCa.

The new taxane cabazitaxel will overcome potentially existing intrinsic and extrinsic chemoresistance to docetaxel and it might thereby improve the prognosis. Cabazitaxel is a novel taxane and preclinical results have shown cabazitaxel to be highly effective against docetaxel-resistant cell lines and tumours [8-13]. Furthermore, cabazitaxel unlike other taxanes has been shown to pass the blood-brain barrier in vivo thereby being potentially active in patients with cerebral or leptomeningeal metastatic disease [13].

The drawbacks of all the clinical trials performed are the following:

· heterogeneous patient cohort due to the inclusion criteria of the D’Amico classification

· clinical staging without the application of modern image techniques such a multiparametric MRI allowing the identification of high patients with extracapsular extension and/or seminal vesical invasion

· non standardized techniques of radical prostatectomy and/or pelvic lymphadenectomy which have to performed in an extended resection technique without nerve sparing procedures

· no reference uro-pathologists with high experience in prostate cancer pathology

· no evaluation of molecular markers in the prostate biopsy samples which might be associated with response to treatment or with the development of docetaxel resistance

The current trial might overcome the drawbacks of the past trials due to the following decisions:

· inclusion of a homogenous patient cohort with an identical high relapse risk ≥ 60% by applying the Kattan nomogram

· preoperative clinical staging by initial and follow-up multiparametric MRI prior to chemotherapy and prior to radical prostatectomy in order to identify complete or clinically significant partial remissions

· standardized surgical technique performed by one single, highly experienced surgeon (> 1500 radical prostatectomies)

· reference pathology of prostate biopsy and radical prostatectomy specimens

· evaluation of molecular markers and histopathological parameters and their correlation with response