6. Treatment of non-metastatic prostate carcinoma – Prostate Cancer

Background information

The above recommendations are intended to support communication with the patient and to support them in their treatment decisions. If the tumor is clinically non-metastatic, the physician and patient must decide together whether a local and potentially curative treatment should be given or not. 

Re: Recommendation 6.1

When providing information to the patient, the physician recognizes patient autonomy; this corresponds to the principles of good clinical practice. For advantages and disadvantages of each option, see background information points 6.4 and 6.7. 

Re: Statement 6.2

A systematic review of studies which included several thousand men with a diagnosis of prostate cancer with a focus on level of anxiety and its management showed that events such as an upcoming medical examination and checking of the PSA level induced anxiety that decreased again after a normal test result [308]. The anxiety associated with repeated PSA testing and the repeated (anticipated or actual) decision-making events mean that up to 10 % of men under Active Surveillance undergo a curative treatment despite this not being required on the basis of the tumor progression [309]. On the basis of the data available, no response can be given as to whether factors such as active information seeking, social support, and cognitive reframing of the situation reduce uncertainty and anxiety in the long term and improve quality of life.

After a PCa diagnosis, the observation can be made that a high percentage of men (both after RPE and also those under Active Surveillance) make at least short-term lifestyle changes. Men who are yet to make a decision to follow Active Surveillance, and those under Active Surveillance seem to represent a special patient population in this regard. Since passive waiting is associated with increased stress [310], it can be assumed that men following this treatment approach have an even higher willingness than surgically-treated men to maintain their quality of life, and reduce their anxiety about their disease, as well as to seek complementary treatment options and/or make lifestyle changes (diet, physical activity, complementary medicine interventions) [311]. Several studies show that additional strategies, such as a special diet or even complementary medicine treatments, are most likely to be discussed with the female partner (e.g., [312]. Among men, female partners are mentioned as the most important source of support (see also Van den Bergh et al. [313][314]).

From the available data it can be concluded that the wait-and-see approach is often difficult for patients. The approach of "going active" is internationally recognized. This is often also a desire also exists among family members and in wider social circles. Last but not least, there is a lack of medical support for patients under Active Surveillance [315]. Questionnaire studies in a group of patients under Active Surveillance showed only slightly more distress, anxiety, and depression at most six months after diagnosis compared to healthy individuals. Over time, however, the scores became worse [316] [317]. The dominant theme was uncertainty and fear of uncontrolled tumor growth, which was greatest at the follow-up appointments. In qualitative interviews, the supervising physician was attributed the greatest influence over the decision to apply Active Surveillance, followed by fear of side effects in case of active treatment [311] [317] [318]. However, over time, it also appears that a very large influence on the part of the physician in the decision can be negative [317]. The treating physician should have an open ear for the patient's individual information needs and be trained to practice strategies with them to cope with uncertainty [319]. Data from cross-sectional/case-control studies do not show poorer quality of life of patients under Active Surveillance compared to patients receiving radiotherapy and/or hormone-ablation therapy [320] [321]. There are no prospective comparative data available. 

Re: Statement 6.3

Palliative treatment strategies with no curative intent are considered in this section. The planning of a treatment strategy always involves weighing up the benefits against the risks. The WW strategy and palliative measures should be explained to the patient: e.g., hormonal cascade, interventions for hemostasis, radiotherapy for pain, palliative Turp for bladder emptying dysfunction. Indication: localized, low-aggression tumor, limited life expectancy. In the HTA report by Ip et al. [307] over 70 % of these patients were in the T2 category, Gleason ≤ 7, normal bone scan, age < 75 years, only in one study < 85 years. Symptomatic progression [322] is considered an indicator of treatment. Since Gleason ≤ 7 is mentioned as an indication for WW, it can be indirectly inferred from this that poorly differentiated tumors can be immediately treated systemically.

Since prostate cancer is generally a slowly progressive disease with long overall survival even without therapeutic intervention, the years of life gained as a result of treatment must be weighed up against a loss of quality of life due to the sequelae of treatment. It should be mentioned that at a more mature age there is a high risk of decompensation of bladder function after local therapeutic interventions (radical prostatectomy, percutaneous radiotherapy, brachytherapy). Thus, 2 years after inclusion in a study, significantly more patients undergoing radical prostatectomy reported decompensation of bladder function than patients undergoing palliative treatment [306]. 

Even with a high risk of progression, a palliative approach is possible. Therefore, the risk of progression should be addressed and discussed in every case. In addition to the risk stratification by D’Amico et al. 1998 [D'Amico, A.V. et al. 1998], validated nomograms are available that can be used to estimate the risk of progression (see chapter 5 on diagnostics and staging).

The PIVOT trial (RCT, 2012) compared radical prostatectomy and Watchful Waiting in patients with prostate cancer detected predominantly by means of PSA screening (median age 67 years) [306]. The long recruitment period (1994-2002) is seen as a potential weakness of the study, as diagnostic and therapeutic procedures have since evolved. The originally planned number of subjects could not be reached (planned: 2000, recruited 731 patients, revised power calculation 91 % power for detection of a 25 % difference in all-cause mortality at a mean life expectancy of 10 years). Assigned cause of death "prostate cancer" cannot be considered certain [323]. As a result, for patients with a PSA level 10ng/ml (median 15) was in favor of RPE (relative reduction of 13.2%, HR: 0.67; 95% CI: 0.48 – 0.94). Furthermore, significantly fewer bone metastases were diagnosed after RPE (n = 17, 4.7%) than under observation (n = 39, 10.6%, HR 0.40; 95% CI: 0.22-0.70; p < 0.001).

For adverse effects, see Recommendation 6.4.

Re: Recommendation 6.4

In patients with low-risk carcinoma, no higher or only slightly increased mortality was demonstrated when following an observational treatment strategy (WW) compared with prostatectomy [305] [306]. This slight superiority is contrasted with the risk of overtreatment (see also background information on section 6.2) with adverse effects and therapeutic consequences. Patients should be informed about these aspects. 

From the time-limited data to date, there is no worse prognosis under Active Surveillance [324]. Of 2,079 men in the PRIAS study, 189 underwent RPE. Pathologic results were available for 167 patients: 71% had favorable histology (defined as pT ≤ 2 and GS: 3+4), 81% had organ-confined tumor, and 86% Gleason 6 or 3+4.

Specific comparative data on adverse effects and treatment consequences of each locally curative procedure are problematic due to the lack of comparative studies. Adverse effects are also defined in very different ways [325]. Toxicity figures from case series are not directly comparable because of the different patient collectives. Finally, the numerical values differ depending on whether surveyed patients or treating physicians collected the data. 

A proposed recommendation whereby overtreatment was stated along with the consequences of urinary incontinence and erectile dysfunction after prostatectomy and bowel dysfunction after radiotherapy was not supported by the majority of authors of the guideline because the side effects were not listed in a sufficiently differentiated manner, although education on these aspects is considered essential. 

The following is an overview of the most frequently mentioned adverse effects/diseases in the literature depending on the therapeutic strategy. The most serious adverse effects and consequences of local therapy for prostate cancer are sexual dysfunction in the form of erectile dysfunction, disturbances of continence and urinary bladder function, and colonic and rectal disorders. 

To adequately assess the extent of erectile dysfunction, pretherapeutic data would be of interest for comparison, as the prevalence of erectile dysfunction is by nature not insignificant in the older patient population. These data are mostly lacking. Nevertheless, from the published postinterventional prevalence rates, it can be concluded that the probability of erectile dysfunction occurring is higher after radical prostatectomy than after percutaneous radiation [190] [325][326][327]. Short-term results on sexual function even under Active Surveillance from Van den Bergh [328] 6 and 12-18 months after treatment showed that 65-68% of men under Active Surveillance, 35-36% of those undergoing surgery, 36-37% of those under radiotherapy, and 36% of those receiving combination treatments were sexually active. 

Urinary incontinence or retention is more common after radical prostatectomy than after percutaneous radiotherapy or LDR brachytherapy. Data comparing percutaneous radiotherapy and LDR are sparse. In a cohort study [329], LDR brachytherapy also compares more favorably with percutaneous radiotherapy.

Intestinal symptoms (e.g., increased stool frequency, rectal bleeding) occurs more frequently after percutaneous radiation or brachytherapy than after radical prostatectomy [96] [190] [326] [327] [330]. A comparison between LDR brachytherapy and percutaneous radiotherapy is difficult to make due to limited data. However, there is evidence for an advantage of LDR brachytherapy over percutaneous radiotherapy with respect to rectal function [331]. An assessment of toxicity for HDR brachytherapy is possible based on case series – but a direct comparison of the procedure with radical prostatectomy, percutaneous radiotherapy or LDR brachytherapy has not been made in the context of studies. In this regard, reference can only be made to the absolute numbers cited in the studies [332] [333]. The risk of rectal discomfort, incontinence or urinary dysfunction and erectile dysfunction is also a factor with this treatment option. 

A side effect specific to radiotherapeutic procedures is the occurrence of secondary malignancies. According to studies, the risk is significantly increased for percutaneous radiotherapy [334][335][336] . For LDR brachytherapy, one paper found a lower risk in comparison, but the difference with percutaneous radiotherapy was not statistically significant [337]. In another paper, the rate of secondary malignancies was also lower overall for LDR brachytherapy, but it should be noted that the hazard ratio for percutaneous radiotherapy was constant at 1.26/100,000, but the hazard ratio for LDR therapy increased from 0.72/100,000 at five years to 1.2/100,000 at nine years [338]. However, the incidence of second malignancies, as shown by the above figures, is thereby significantly lower than those of the other adverse effects mentioned. For HDR brachytherapy, no long-term data exist (yet). 

The adverse effects of hormone-ablation therapy can be found in the corresponding chapter. 

Re: Recommendation 6.5

This recommendation takes into account the fact that due to the limited evidence available, it is not possible to prioritize a local treatment option without randomized-controlled cross-interventional comparisons. This fact is confirmed in both the 2007 AUA guideline, the EAU guideline, and the Dutch guideline [96] [190] [191]. The only procedure that has been studied in the context of a randomized trial design versus a watchful waiting strategy is radical prostatectomy. The efficacy claims of the other local procedures are based on comparative cohort studies (percutaneous radiotherapy, LDR brachytherapy) or even case series comparisons (HDR brachytherapy). When evaluating the RCT by Bill-Axelson et al. [339] on the value of surgical therapy, it should be borne in mind that the cancer-specific survival benefit only concerned patients aged less than 65 years and that the patients were from the pre-PSA era. In view of this situation, the choice of local therapy procedure crucially depends on individual characteristics and the personal preferences of the patient. 

In order to select the most appropriate procedure in this process from both the physician's and the patient's point of view, it is recommended that the patient discusses treatment options with both the urologist (RPE and LDR brachytherapy, but also regarding the strategy of Active Surveillance or the secondary symptom-oriented therapy Watchful Waiting) and the radiotherapist (percutaneous radiotherapy and HDR brachytherapy). These explanations should also include possible multimodal treatment concepts. The affected patient will thus be fully informed about the advantages and disadvantages of the various procedures. Since the choice of local therapy often also depends on the preferences of the physician(s) providing the information [307] [340], it is considered useful to provide information about additional information sources available. In recognition of the fact that it is not always feasible to give information on two seperate occasions for personnel and organizational reasons, a lesser recommendation grade (B) was assigned. However, a dual approach to patient education is explicitly considered to be desirable.

Re: Recommendation 6.6

The health status of patients of the same age varies considerably. Comorbidities are one area to systematically capture this heterogeneity and their impact on survival. Various classifications are available for the systematic recording of comorbidities. 

So far, few recommendations on the practical use of comorbidity classifications can be found in the available guidelines [69] [101][191]. Only the EAU guideline mentions the Charlson score and ASA classification as decision aids for prostate biopsy [69]. Based on this recommendation, both classifications were included in the S3 guideline. 

Among relatively healthy candidates for radical prostatectomy, even in patients 65 years of age or older, the comparative mortality at 10 years is still less than 50% in the least favorable classes of these classifications [345]. That is, the median further life expectancy is above 10 years even in these subgroups, a cutoff often cited as the limit for curative treatment for prostate cancer [69]. 

The association between a comorbidity class and survival varies greatly depending on whether the sample is a population-based sample (contains all risks), a radical prostatectomy sample (contains predominantly good risks), or a radiotherapy sample (may contain many unfavorable risks). There is a lack of generally accepted criteria for delineating these respective cohorts. This is clearly illustrated in the very large survival differences between patients undergoing surgery and radiotherapy in nominally identical risk classes in a nomogram by Walz et al. [341]. This points to the inadequacy of the nomogram, which takes into account age, comorbidities, and therapy (radical prostatectomy vs. external beam radiation) but no other variables beyond that. Therefore, comorbidity classifications and associated survival rates can be used to make treatment decisions in prostate cancer only by considering the underlying patient populations. Furthermore, increasing life expectancy and possible lead-time bias should be considered. The remaining life expectancy of a 65-year-old man increased from 14.4 to 17.3 years between 1990/92 (former West Germany) and 2008/10 [346]. At the same time, PSA-based screening can be expected to lead to an earlier diagnosis (lead-time bias). With a four-year screening interval, a diagnosis lead-time bias of 11 years can be expected [347]. Conclusions from older patient samples must therefore be applied with caution to today's patients: the tumors are detected earlier (and therefore are possibly indolent for longer), but the remaining life expectancy has increased at the same time, whereby in the absence of curative therapy the time a tumor has for progression increases. In this context, the increase in life expectancy mainly affects men beyond the age of 65 [348] [349]. 

Not all men who develop prostate cancer (PCa) over the course of their lives have to expect a reduction in their life expectancy or quality of life associated with their cancer. This is a well-known phenomenon, autopsy studies conducted decades ago showed that the number of "carcinoma carriers" is many times higher than the number of those who develop or die from PCa [358]. 

In recent years, PCa diagnosis has changed significantly, whereby many carcinomas are detected earlier. The determination of the PSA value is used more frequently. In addition, the threshold of PSA for biopsy indication is increasingly lowered and PSA trends over time as well as age-correlated PSA thresholds and more extended biopsy schemes are used for diagnosis. As this creates a risk of overdiagnosis, it increases the rate of supposedly curative therapies. Overdiagnosis is when carcinomas are discovered that do not threaten the patient's life expectancy. Treating these results in overtreatment. A high proportion of overtreatment results mainly from definitive treatments in a group of patients with low-risk tumors. In the European screening study, the proportion of overtreatment measured after nine years of follow-up was 54 % [359]. The problem of overdiagnosis and overtreatment must therefore be increasingly discussed and taken into account [360].

Several definitions have been developed and published to distinguish clinically significant PCa from non-significant PCa. [361] Depending on how strictly each definition is applied, 4 to 19 different definitions of "insignificant" prostate cancer can be found [78], [280], [362], [363], [364], [365], [366], [367], [368], [369], [370], [371], [372], [373], [374], [375], [376], [377], [378], [379], [380], [381], [382], [383], [384], [385], [386]; With the exception of one publication [361], all definitions are based on the 1993 work of Stamey et al. [384], who report volume alone as a criterion for clinical significance of a tumor. Gleason stage and limitation to the organ were added later and are used inconsistently (volume < 0.5 or ≤ 0.5, Gleason < 7)

Separate to the various histologic definitions of a tumor that is not clinically significant, there are "prediction tools" for histologic findings and prognosis. These instruments contain varying parameters that are used to predict the presence of a non-clinically significant PCa. The reliability of each "instrument" varies – but none prospectively detects a clinically or anatomically non-significant PCa with sufficient certainty. This was also the conclusion of the elaborate systematic review by Harnden et al. (2008) [387], in which all available volume definitions were correlated with clinical course parameters (extracapsular growth, R1/2 status after RPE, PSA recurrence after RPE, PSA recurrence after percutaneous radiotherapy). 

As tumors not requiring treatment cannot be characterized with certainty on initial diagnosis, other strategies are being pursued to avoid potential overtreatment. The two approaches used for this purpose are discussed below.

The frequently routine determination of the PSA value often leads to the detection of tumors for which the same tumor-specific survival can be achieved with no treatment as with definitive invasive therapy [356]. This is especially true for older patients (> 65 years). Tumor-specific survival of patients with low-risk profile tumors without definitive intervention is very high [305] [355].

In prostate cancer, Watchful Waiting is understood to be long-term observation with delayed palliative care and symptom-oriented therapy [69] (also referred to as deferred or symptom guided treatment). By definition, Active Surveillance in otherwise healthy patients who are suitable for curative therapy aims to postpone timely active treatment until a point in time when there are indications of progression or when the patient wishes to undergo such treatment [322]. The aim of therapy for in the event of progression is curatively intended [69]. For this purpose, close monitoring of progression with defined progression parameters including follow-up biopsy is performed. The aim of Active Surveillance is to reduce overtreatment of early tumor stages without lowering cure rates. 

Two randomized trials compared Watchful Waiting with radical prostatectomy [69] [306]. However, in the control arm of both studies, the therapy was not a purely palliative symptom-oriented therapy, but a mixture of Watchful Waiting and (unstructured) Active Surveillance, which is reflected in a not insignificant rate of treatments with curative intent in the control arm.

The recommendations on Active Surveillance are based on studies of limited methodological quality (older studies, some retrospective, some involving small numbers of cases, different selection criteria and short observation periods). More recent studies are generally prospective and have median follow-up times of between 3.7 years and 7.8 years (see table and evidence tables for the guideline). All studies have consistently high tumor-specific survival rates (see table). Prospective randomized therapy-comparative trials (PROTECT, START, PRIAS) will not be completed until 2023. Differences in overall survival cannot be expected due to insufficient case numbers (insufficient power). Defensive strategies in the management of PCa patients require intensive follow-up in terms of consultations and care. A decision for Active Surveillance can only be made by the physician and patient acting together following a detailed discussion. The option of seeking a second opinion should also be offered.

In the study by Bill-Axelson et al. (2011) [305], which included patients with palpable tumors and significantly elevated PSA levels, tumor-specific death was statistically significantly more common in the group not undergoing primary treatment after 15 years, with 6.1 % more deaths. The difference in overall survival was 6.6 % less in favor of surgery (46.1 % RPE vs. 52.7 % WW). This difference is not statistically significant as an absolute difference, but rather only as a relative difference (relative risk reduction 25 %). Patients younger than 65 years showed a larger difference of 13.5 % (33.9 % RPE vs. 47.5 % WW). Patients 65 years and older did not benefit from surgery in terms of either tumor-specific or overall survival in the subgroup analysis. 

The PIVOT trial included many patients diagnosed by PSA-based screening. In this study, no statistically significant difference was found between observation and RPE in terms of prostate cancer-specific mortality at 10 years (31 vs. 21 cases). In the subgroups, there was no significant difference in overall survival in patients with PSA < 10ng/ml (median 6; HR 1.03; 95% CI: 0.79-1.35), but a significant difference in overall survival in patients with PSA >10ng/ml (median 15) in favor of RPE (relative reduction of 13.2%, HR 0.67; 95% CI: 0.48-0.94). There was a significant reduction in the incidence of bone metastases in favor of RPE: 17 (4.7%) vs. 39 (10.6%) under observation (HR 0.40; 95% CI: 0.22-0.70; p<0.001). Problems with the PIVOT trial include the following: the long recruitment time, the number of cases lagging behind the baseline design, and the high relative mortality of over 30% at 10 years (for comparison, see [392] [393]).

The NIH statement on Active Surveillance, based on an evidence report, refers to it as a "viable option" for patients with a low-risk tumor [393]. However, it also identifies a significant need for research. In addition to improvements in diagnostic certainty due to the availability of more predictive markers, it also addresses the optimal protocols for Active Surveillance (in terms of intensity/invasiveness of surveillance and detection of progression), the influence of socioeconomic and psychological factors on progression and decision-making processes), and data collection on the comparative effectiveness of Active Surveillance compared to immediate local therapies in young patients with a long life expectancy. This need for research has also been identified by the guideline group.

Re: Recommendation 6.7

In localized PCa, patients eligible for curative therapy should be informed about immediate local therapy options such as radical prostatectomy (RPE), percutaneous radiotherapy (RT), and brachytherapy (BRT), as wellas taught about the concept of Active Surveillance. Prioritization of Active Surveillance is supported by some guideline group members but not shared by the vast majority of the guideline group. As part of patient education, the natural prognosis of patients with low risk profiles should be compared with the outcomes of active treatment modalities. This concerns mortality, morbidity, and quality of life (e.g., necessary follow-up, possible avoidance of overtreatment), as far as is known. Recurrence rates for treatments with  curative intent should also be explicitly addressed, as well as the existing uncertainty regarding the primary prognostic assessment of diagnosed carcinomas that exists for each type of primary therapy/strategy. Thus, rates of understaging and overstaging in low- and intermediate-risk tumors have been described as ranging from approximately 20 % to approaching 50 % percent [394], [395], [396], [397], [398], [399]. Adverse events are discussed in the background text to recommendation 6.4.

The randomized ProtecT trial (n = 1643) compared Active Surveillance, radical prostatectomy, and radiotherapy as primary treatment options. Mortality data at 10 years showed that the majority of all three groups were alive; prostate cancer-specific survival was at least 98.8% in each case and did not differ significantly. In contrast, the incidence of metastases was significantly higher in the group without primary radical treatment than in the groups with prostatectomy or radiotherapy (Active Surveillance 33 cases, prostatectomy 13 cases, radiotherapy 16 cases). Within the observation period of the study, 55% of patients from the Active Surveillance arm received radical treatment. No subgroup analyses were performed in the publication [350]. The study population consisted predominantly of patients with low and, in some cases, intermediate risk profiles (10% of patients had an initial PSA greater than 10 ng/mL; 77% had a Gleason score of 6, 21% had a GS of 7, 2% had a GS 8-10; 76% with tumor category T1c, 24% with T2).

Indirect evidence from the Bill-Axelson 2011 data, with respect to metastases, indicates that at 15 years, 66.6% of patients without immediate treatment had no evidence of distant metastases. 21.4% of those treated had distant metastases after primary surgical treatment [305]. No further RCT’s are recommended by the expert panel of the NIH report to address mortality issues, but it was recommended that future studies focus on health-related quality of life and morbidity of different Active Surveillance strategies [400]. 

The adverse effects of Active Surveillance (e.g., sequelae of biopsy) have not been adequately studied to date. 

Re: Recommendation 6.8

Before discussing Active Surveillance with a patient, it should be determined whether the patient has a tumor with the appropriate characteristics. The inclusion criteria mentioned in the recommendation correspond to an expert consensus based on the work of Klotz and Bastian [351], [352], [353]: PSA ≤ 10 ng/ml, Gleason ≤ 6, cT1 and cT2a, tumor in ≤ 2 biopsies with guideline-compliant sampling of 10-12 biopsies, ≤ 50% tumor in one biopsy. 

The studies listed in the review [Dall'Era, M.A. et al. 2012] show that overall no uniform criteria are used (also included are: PSA value < 15 ng/ml (Royal Marsden Hospital), Gleason ≤ 3+4 (Royal Marsden), positive biopsies: ≤ 33 %, ≤ 50 %, ≤ 2, ≤ 3, tumor extent per biopsy ≤ 50%, ≤ 20%). A further compilation on inclusion criteria can be found in Bul et al. [68] and in the EAU guideline [69]. A summary of Active Surveillance criteria from eleven studies is provided in table 3 of the AHRQ report [307]. 

Inclusion of Gleason 6 tumors is uncontested and equally chosen as criteria in all studies. The term "cancer" is used when discussing this tumor [402]. With respect to this discussion, the studies available on this subject were assessed as being indicative, but not as conclusively-validated evidence. A good example is the work by Ross et al. [403]. Here, a database of 14,123 prostatectomy specimens from patients with Gleason score ≤ 6 was analyzed. Lymph node metastases were described in 22 cases, of which n = 19 were available for reevaluation. All of the examined specimens were ranked higher on reevaluation (GS 3+3 (tertiary pattern 4): n = 3; GS 3+4: n = 12; GS 4+3: n = 1; GS 4+5: n = 1). Since only the specimens with documented lymph node metastases and Gleason ≤ 6 were analyzed, we consider the study to be clearly indicative and not as hard "evidence" for Gleason 6 tumors not metastasizing. 

The proportion of tumor identified in the biopsies is considered by the guideline group to be set at a relatively restrictive level, unless 10-12 biopsies are performed in principle (i.e., > 12 biopsies). Alternatively, therefore, following the protocol of the PREFERE study [404], a proportion of tumor of < 30% was discussed as a possible option. A different weighting for multifocality (e.g., detection in all four quadrants) was also discussed. In a retrospective, exploratory analysis of a hospital database of patients following prostatectomy, a higher number of positive biopsies was considered acceptable if the other criteria were in favor of low risk, as no increased rate of negative pathologic findings was noted [405].

Other criteria used in the series (including PSA velocity, PSA density) are not yet considered to have been studied prospectively enough to be recommended [406], [407], [408]. The authors also believe that insufficient data are available for DNA cytometry to justify its routine use as a predictive marker for active therapy. Information on PSA doubling time (PSADT) is usually not available at the time of indication, therefore this parameter is not regularly applicable as a criterion for indication in routine practice.

Special cases

• The PSA value after TURP must be evaluated accordingly.
• In patients with incisional prostate carcinomas who are potentially candidates for Active Surveillance, the actual tumor extent should be assessed by means of a short-term control biopsy before a treatment decision is made.
• Very small tumors, defined as unifocal tumors < 1 mm are not considered as requiring treatment by the guideline group

Active Surveillance in patients with Gleason 3+4 (7a): 

Both the 2005 AUA guidelines and the 2008 NICE guidelines recommend discussing the Active Surveillance strategy with patients as a treatment option even if they are at intermediate risk [101], [191], [409]. The NIH report identifies a need for further research for this patient group [400]. Expanding the inclusion criteria to Gleason 3+4 (7a) according to the protocol of the PREFERE trial [404] is supported by some members of the guideline panel. The rationale for this, in addition to serial data, is the assessment that reclassification of the Gleason score (ISUP 2005 [410]) results in an upgrade from Gleason 6 to Gleason 7a in approximately 30%. The vast majority of the guideline group considers Gleason 3+4 (7a) not suitable as a routine inclusion criterion for Active Surveillance due to potentially higher malignancy and no reliable criterion for differentiation in this regard. Further testing as part of clinical trials is considered necessary. 

The following data are available on this issue: 

In a Canadian cohort study, of 450 patients under Active Surveillance, 85 (18.9%) had intermediate-risk tumor (Gleason 7 or T3 or PSA > 15 ng/ml). Of these, 49 remained untreated without progression and 36 were treated. Of the 36 treated, one patient progressed [353]. 

In the Swedish tumor registry, the low and intermediate risk group (Gleason ≤ 7, PSA up to 20 ng/ml, T2) is evaluated together under Active Surveillance and the tumor-specific 10-year mortality is reported as 3.6% [411].

In the PIVOT study, subgroups included T1 vs. T2 and Gleason 6 vs. 7-10 (40% low, 34% intermediate, and 21% high risk) were compared. The benefit in reducing PCa-related mortality was 2.6% across all risk groups and was not significant [306]. 

The results of prospective studies with follow-up of at least five years to date show no difference in outcome of patients with Gleason score 7 (intermediate risk) compared with Gleason score 6 when Active Surveillance is used (see table).

Re: Recommendation 6.9

The control intervals and examinations followed during Active Surveillance vary in the literature [352]. The present recommendation corresponds to an expert consensus.

Regular patient contact and careful tumor monitoring are necessary as part of an Active Surveillance strategy because tumor progression may occur, or patients, without becoming symptomatic, may wish to be given advice regarding curative treatment. In studies available in the literature with a median follow-up of at least five years, 30-59.8% of patients received active therapy (see [Dall'Era, M.A. et al. 2008]). The proportion of active therapies at the patients' request in the available studies is 8-17% [353], [391], [413], [414]. In the ProtecT trial with 10 years of follow-up, 54.8% of patients in the monitoring arm underwent radical treatment during the course of the trial [350].

It is unclear whether the changes in histology during follow-up are due to tumor growth, de-differentiation or misinterpretation of the initial biopsy. Therefore, a second biopsy should be performed as a control with respect to the initial findings. The recommended time interval to start Active Surveillance depends on whether MRI with targeted biopsy has already been performed prior to the decision (for MRI in primary diagnosis, see recommendations 5.13, 5.14, and 5.18). For patients with initial MRI and targeted as well as systematic biopsy, the expert group recommends a repeat MRI-guided biopsy and systematic rebiopsy (again in combination with MRI imaging) after 12 months. Existing data on MRI-guided biopsy indicate a lower rate of misclassification, so a period of one year is considered reasonable here. In patients who have not had MRI, a combination of MRI-guided and systematic rebiopsy is recommended to reduce the risk of underdiagnosis as early as at 6 months, but no earlier than 8 weeks after punch biopsy to minimize biopsy artifacts. The lower level of recommendation was chosen because of the lack of high-quality direct comparison studies for the different time intervals. In study cohorts under Active Surveillance with short follow-up (median follow-up between 1.8 and 3.9 years), the median time to treatment ranged from 1.3 to 3.5 years [Dall'Era, M.A. et al. 2008]. In a study with a median follow-up of 6.8 years, half of all progressions under Active Surveillance occurred in the first 2 1/2 years. [353] . In another study, 21.5% of tumors had to be upgraded after only 1 year [68]. These data suggest inadequacies of the conventional initial biopsy. To date, evidence on the long-term benefit of new monitoring strategies in terms of patient-relevant outcomes is lacking. There is evidence from comparative cohorts that MRI reduces the likelihood of subsequent upgrading [181], [183]. 

During the remainder of Active Surveillance, it is recommended, as in the past, that rebiopsies be performed every 12 to 18 months for the first three years and every three years thereafter if the findings are stable. Evidence on the value of MRI in the context of AS monitoring is insufficient to date. If a lesion was previously identified on MRI, the expert group believes that annual MRI checks with rebiopsy should be performed in case of progression of clinical or imaging findings, if the attending physicians / the attending center are equipped to do so. In the case of an inconspicuous MRI and stable clinical parameters, however, the authors advocate a procedure analogous to the PRIAS project with further MRI checks and rebiopsies every three years. 

Re: Recommendation 6.10

The doubling time of the PSA value is increasingly used as a criterion for establishing the indication for active therapy. In this context, the data from the literature is not consistent: some analyses have demonstrated a statistically significant association with prognosis [351], [353], [389]. With a short follow-up time, evidence of this could not be found in the work of Ross [415] and Kakehi. Even a doubling time of the PSA value of less than twelve years can signal progression [416]; if it is less than 1.5 years, the tumor will have progressed in half of the patients within six months [357]. 

Klotz et al. 2010 [353] were able to confirm a statistically significant correlation with prognosis at a cutoff of three years after 7.8 years. Therefore, in accordance with the approach of Klotz et al. a therapeutic intervention with a curative intent is considered necessary if the doubling time of the PSA value is reduced to less than three years or the grade worsens to a Gleason ≥ 7 (4+3). Prospective comparative validation of cutoff values is pending.

PSA density did not yet appear to have been sufficiently studied in order to be included as a criterion for active therapy [417]. Other markers (PCa3, fPSA/PSA ratio) have not yet been evaluated for their suitability as markers for active therapy.

Re: Recommendation 6.11

Watchful Waiting should be discussed with elderly patients who may not be eligible for curative treatment because they have greater comorbidities or a presumed life expectancy of less than ten years (in one study < 15 years). The T category is arbitrary, as is the PSA level, and the Gleason score should be ≤ 7 [355], [356], [357]. Only tumor symptoms matter for the timing of delayed palliative intervention [322]. 

The determination of life expectancy corresponds to an assessment that should be discussed together with the patient. When comorbidity indices are used to determine continued life expectancy, always consider the population in which the index was developed or validated when considering predicted mortality rates. Comparative mortality can vary considerably even between collectives of comparable age and comorbidity structure, due to prior selection bias. A universally accepted instrument for measuring comorbidity in prostate cancer does not yet exist. The Charlson score has been cited most frequently to date (see also recommendation 6.6). 

The International Society of Geriatric Oncology (SIOG), after systematic review of the literature to determine life expectancy in elderly patients, recommends assessing comorbidities (cumulative Illness score rating - geriatrics), determining the degree of dependence in daily living (instrumental activities of daily living), and assessing nutritional status [418].

Background information

Summary of the evidence base

The literature reviewed on the treatment of lymph node-positive prostate cancer is as follows:

Mainly retrospective case series with insufficient risk adjustment (with regard to prognostic factors such as T-category distribution, Gleason score and especially with regard to the number of affected lymph nodes) have been found. 

As of 2000, the following RCTs on the topic were identified:

• Schröder F.H. et al. 2008 [686]: immediate versus delayed endocrine treatment alone for lymph-node-positive prostate cancer. According to the study protocol, the RCT was designed to demonstrate non-inferiority of delayed endocrine treatment. The study has an insufficient number of cases with respect to this evidence because the patients were not all randomized. It is also too small in terms of demonstrating a benefit of immediate endocrine treatment. It was also not designed for this purpose.
• Lawton et al. 2001/2005 [687], [688]: retrospective subgroup analysis of RTOG-85-31 RT comparing immediate endocrine therapy following radiation vs. endocrine therapy only for treating a recurrence in (histologically confirmed) lymph-node-positive patients.
• Kleeberg et al. 2000 [689]: RCT comparing immediate versus delayed endocrine therapy in lymph-node-positive patients. The RCT has a small number of cases and thus test strength (power).
• Iversen et al 2004 [690]: retrospective exploratory pooled subgroup analysis for 150 lymph-node-positive patients from three trials totaling > 8,000 patients (57% histologically-confirmed, 43% diagnosis based on imaging): bicalutamide versus placebo. Preliminary results only, no measurement of survival data.
• Messing et al. 2006 [691]: RCT comparing immediate versus delayed hormone-ablation therapy in lymph-node-positive patients (n=98) with a median follow-up of 11.9 years. The RCT showed a statistically significant benefit in terms of progression-free survival, disease-free survival, and overall survival.

Consequently, the analyses from RCTs outlined here present methodological weaknesses.

With respect to the value of prognostic factors in lymph node-positive carcinoma, a population-based study was identified [692]. In this case, only the degree of differentiation (Gleason score/WHO grading) of the tumor was found to be borderline significant in the multivariate analysis. 

The following treatment options were investigated in the present studies (including any study quality): 

1. surgical therapy alone;
2. surgical therapy and androgen ablation;
3. surgical therapy and radiotherapy;
4. androgen ablation alone;
5. radiotherapy alone;
6. radiotherapy and androgen ablation;
7. additive chemotherapy;
8. combined forms of therapy.

The lymph node metastases in the studies have not always been histologically-confirmed, which implies uncertainty in the assessment of the effects achieved. A valid comparison of the therapy options cannot be performed on the basis of the available studies. 

For the option of additive chemotherapy, only one phase-II trial and two phase-III RCTs with small numbers of cases and marginal effects are available, so that this therapy option must be considered as experimental [693], [694].

There seem to be regional or national differences in the choice of primary approach. For example, Aus [692] states for their population-based analysis that in Sweden a consensus has been reached to treat primarily with an endocrine approach when lymph node metastases are detected and to forgo local therapy. The NICE guideline [101]  includes primary local radiotherapy in its recommendation on the approach to increased risk of lymph node metastases and recommends endocrine therapy as an add-on treatment. However, no recommendation is made regarding patients with histologically proven lymph node metastases. The recommendation in the EAU guideline [96] is similar in content to the recommendation in the NICE guideline.

Re: Statement 6.63

The literature review (see literature citations Swanson et al. 2006 [678]) shows superiority of combination therapy (local + hormonal) compared with monotherapy. The limited methodological value of the studies must be taken into account. 

For the question of immediate versus delayed endocrine therapy in lymph node-positive patients, RCTs [686], [687], [688], [689], [691] or (retrospective) subgroup analyses from RCTs are available that show an advantage of immediate endocrine therapy (as sole therapy or as additive therapy), which, however, is not consistently statistically significant. In addition, the studies often have case numbers that are too small for the research question. Therefore, due to the state of the literature available, therapy recommendations are subject to uncertainty. 

From the few studies that make a differentiation according to the number of affected lymph nodes or with regard to micro- or macrometastases, a negative correlation can be deduced between the number of affected lymph nodes and the prognosis with regard to disease-free survival and overall survival [693], [694], [695],[696], [697].  

Briganti et al. 2009 [696] demonstrated in a consecutive series (n=703) with a median survival of 9.5 years that tumor-specific survival was significantly worse with more than two affected lymph nodes than with less than two affected lymph nodes (62% versus 84%; after adjustment, absolute difference 4.9%, both p < 0.001). This cutoff had already been shown to be significant as a prognostic factor for tumor-specific ten-year survival in a 2007 series (n=507) [697]. In the series by Boorjian et al, a Gleason score of 8-10, positive resection margins, and tumor ploidy (diploid versus non-diploid) continued to be significantly associated with worse prognosis in multivariate analysis. 

Due to of a lack of data on the treatment of patients at increased risk for lymph node involvement, a procedure analogous to that used for proven lymph node involvement is recommended. In principle, lymphadenectomy for histologic evaluation of lymph node status should always be performed in cases of increased risk for lymph node involvement. Only if this is not possible should the risk be estimated using prognostic parameters/nomograms. 

Re: Recommendation 6.64

According to the review of the available literature, the ten-year disease-free survival rate for irradiation alone is 5-48%, which is significantly lower than the data for the combination of radiotherapy and endocrine therapy (57% and 80%). Hormone-ablation therapy alone shows a disease-free survival at ten years of 15-45% [678]. The randomized-controlled four-arm study by Lawton [460] was designed to clarify the timing of hormone-ablation therapy (six months neoadjuvant/adjuvant to radiotherapy or six months adjuvant) and the additional effect of radiation to the pelvic lymphatic ducts in patients at high risk for lymph node involvement (> 15%) and receiving percutaneous radiotherapy. The study showed inconsistent results regarding the timing of hormone-ablation therapy. The inconsistencies are attributed to unanticipated interactions between the timing of hormone-ablation therapy and radiotherapy [460].

Two prospective randomized phase-III trials that included patients with histologically-confirmed lymph node metastasis can be used to evaluate the duration of hormone-ablation therapy in combination with percutaneous radiotherapy: RTOG 92-02 [679]  and EORTC 22961 [634]. 

For RTOG trial 92-02 (n=1,554), patients with T2c-T4 tumors with PSA levels < 150 ng/ml without evidence of lymph node metastasis outside the pelvis were randomized. The proportion of patients with histologically-confirmed lymph node metastases was low at approximately 3%, but based on the above inclusion criteria, the presumed proportion of patients with non-histologically-confirmed lymph node metastases was relatively high. Both groups received four months of hormone-ablation therapy (goserelin + flutamide, two months neoadjuvant, two months concomitant) plus radiotherapy (45 Gy pelvic lymphatics, 65-70 Gy prostate). The intervention group also received 24 months of adjuvant goserelin. After ten years of follow-up, there was a statistically significant better outcome for the intervention group in terms of disease-free and disease-specific survival, biochemical progression, incidence of local recurrence and distant metastases (all p < 0.001, HR 0.51-0.65), but not for overall survival (51.6 vs. 53.9%).

EORTC trial 22961 (n=1,113) investigated the effect of radiotherapy (50 Gy pelvis/70 Gy prostate) in combination with maximal androgen blockade of six months duration in one arm in patients with T1c-T2b tumors and histologically-confirmed lymph node metastases and T2c-T4-N0-N2 tumors with a PSA of max 40 times the upper normal value. In the other arm, hormone-ablation therapy was then continued with an LH-RH analog for 2.5 years. Approximately 8% of patients had histologically-confirmed lymph node metastases; again, due to the above inclusion criteria, the presumed proportion of all patients with lymph node metastases was relatively high. The primary purpose of the study was to provide evidence that short-term hormone-ablation therapy is non-inferior to long-term hormone-ablation therapy. However, after a median follow-up of 6.4 years, all-cause mortality at five years was 19% in the short-term hormone-ablation therapy group, and 15.2% in the long-term hormone-ablation therapy group (HR = 1.42 and p=0.65 for "non-inferiority"), i.e., survival was clearly improved in the longer-term hormone-ablation therapy group.

Re: Recommendation 6.65

Ten-year disease-free survival rates were up to 24% with surgical therapy alone and 36-76% with surgical therapy combined with endocrine therapy [678]. The data on surgical therapy plus radiation is not sufficiently valid to use for drawing firm conclusions with regard to an expected benefit. It is also possible that adjuvant percutaneous radiotherapy in addition to hormone-ablation therapy may improve cancer-specific survival in patients with histologically-confirmed lymph node metastases following radical prostatectomy. In a consecutive retrospective cohort study of 250 patients, adjuvant radiation of 66.6 Gy (in 26% of prostate metastases, in 74% of prostate metastases plus radiation to the pelvic lymphatic drainage system) was a significant predictor of carcinoma-specific survival, whereby the number of affected lymph nodes was the strongest predictor [681]. The calculated ten-year carcinoma-specific survival rate with adjuvant radiation was 80%, and the proportion of patients with biochemical recurrence-free survival was 53%.

Re: Statement 6.66

The background text to this statement is guided by the previously approved recommendations on the value of lymphadenectomy radiotherapy of the pelvic lymphatic drainage for locally-advanced tumors.

Effect of lymphadenectomy

The therapeutic effect of lymphadenectomy for lymph node metastasis has been studied largely in non-randomized, retrospective studies [680]. According to the review, the results are insufficient to provide a general therapeutic recommendation. Therefore, no generally valid indication can be determined for this procedure on the basis of the existing evidence.

Effect of radiotherapy of the pelvic lymphatic drainage system

For rationale, see background text for Recommendation 6.67.

Re: Recommendation 6.67

With regard to adjuvant radiation in lymph-node-positive prostate cancer after prostatectomy, the update search identified five retrospective studies with medium-sized cohorts, each suggesting a positive effect of radiation. However, due to of relevant methodological problems, these results are questionable: two of the papers [682], [683] are extensions of a cohort already cited in 2009 [681] and therefore share the weaknesses of analyzing patient groups in a non-transparent manner, whereby some of these groups are very different. In particular, the most recent and apparently largest analysis of the cohort (Abdollah et al.) does not show results for groups by matching, but rather it shows them for relatively small and unbalanced subgroups of the overall cohort whereby the proportion of patients receiving radiotherapy is unclear. The differences in cancer-specific and overall survival calculated in only some groups at some time-points partially overlap, and are therefore questionable. Two other retrospective studies analyzed data from the U.S. Cancer Database [685], [698]. In presumably overlapping cohorts, both find comparable effects from additional radiation, with methodological ambiguities as well (significant differences between patient groups, or underreported patient characteristics after matching). The magnitude of the effects (which were relatively small considering the cohort size) should therefore also be viewed with caution. At the same time, all of the studies mentioned share the common feature that the effects point in the direction of an additional potential benefit of adjuvant radiation. One of the identified analyses [684] is methodologically appropriate, but does not allow reliable conclusions to be drawn as a single study and due to the non-separable results (overlapping confidence intervals) with patient characteristics only partially reported. The evidence of prolonged BCR and metastasis-free survival from this analysis should therefore be investigated in prospective randomized trials, as should the potential harms (toxicity rates) not reported by any of the retrospective studies.

Based on the evidence from the retrospective studies, the guideline authors are making a weak recommendation for adjuvant radiotherapy, in combination with hormone-ablation therapy, whereby preferably the patient is included in prospective clinical trials.

Background information

Re: Recommendation 6.74

The recommendation includes three main aspects relating to hormone-ablation therapy (HT) and Watchful Waiting (WW) in nonmetastatic prostate cancer: 

• According to the study by Bill-Axelson et al., WW is inferior to radical prostatectomy in patients younger than 65 years (age at diagnosis) [339]; comparative studies suggest equivalence of percutaneous radiotherapy, LDR, and HDR brachytherapy. WW is not a curative option. HT has not yet been compared with curative therapy, so no conclusion can be made regarding the curative efficacy of HT.  
• Immediate HT is associated with prolongation of progression-free survival [734]. The results for overall survival are inconclusive:
• In the Cochrane analysis by Wilt 2001 [734], a significant benefit in OS is not demonstrated after one, two or five years, but rather only after ten years – the relevance of this treatment for patients with a life expectancy below that level is questionable.
• In the meta-analysis of Boustead 2007 [733], among others, the publication of Studer et al. 2006 [729]  has also been included, and as such the results for survival advantage for immediate HT becomes statistically significant, but the study, in contrast to the Cochrane analysis, purposefully includes other studies and is sponsored by Astra-Zeneca.
• The Medical Research Council (MRC) study from 1997 [730] is one of the pivotal publications to indicate a survival benefit for immediate vs. delayed HT – but the authors themselves point out that the data are not mature; continuous PSA monitoring in patients with delayed HT was not performed, so patients did not receive HT until the onset of symptoms and thus much later in the disease course. This approach is not in line with current standards, as the level of PSA as well as the PSA doubling time should be the condition for initiating HT [736].
• In Iversen 2006 [728], the subgroup analysis of the RCT for the HAT vs WW group showed a significant survival benefit for the T3/4 tumors but not for the T1/2 tumors; with regard to its limitations, the study had been unblinded for the most part, and was then continued as "open label", resulting in a risk of bias.
• In Parker's 1985 [731] analysis of a retrospective cohort, no difference was seen in disease-specific survival and response to therapy with immediate vs. delayed hormone-ablation therapy as part of a WW strategy – however, this study is not randomized, the data are not adjusted for Gleason score or PSA, and M0 and M1 patients were not considered separately.

Thus, the data cannot be considered to be unequivocal. This is the view of both the 2007 EAU guideline ([96], pages 58, 67) and the ASCO guideline which it cites [737]. The Dutch guideline (EBRO) [190] explicitly recommends a wait-and-see approach with regard to the not-insignificant adverse effects (see below), although - contrary to the EAU and ASCO - it comes to the conclusion, with regard to prolonged survival based on the above-mentioned literature, that "RCTs comparing early versus delayed initiation of hormone therapy in patients with locally-advanced prostate cancer showed no difference in disease-free survival and a small advantage in overall survival". 

• An argument in favor of a WW strategy despite proven improvement in progression-free survival with immediate HT is that for cases of palliative care and for cases where there is not a clear overall survival benefit, patients are not expected to deal with the adverse effects of HT until they actually have symptoms due to PCa [732].

Re: Recommendation 6.75

This recommendation explicitly explains the concept of Watchful Waiting and results logically from Recommendation 6.64. 

The question of when to initiate immediate or delayed hormone-ablation therapy was addressed in the retrospective review of the EORTC trial 30891 by Studer et al. 2008 [736]. In the analysis of the EORTC trial 30891, patients undergoing immediate therapy showed a small but significant advantage in terms of overall survival [729]. On the other hand, after a median follow-up of seven years, 50% of patients with planned delayed therapy had not received it, and 25% had already died from causes other than PCa. To differentiate between patients, baseline values and PSA doubling time were examined relative to overall survival and response to therapy. Patients with a baseline PSA level greater than 50 ng/ml are at high risk of dying from PCa and immediate hormone-ablation therapy should be initiated. Patients with a baseline PSA level of less than 8 ng/ml have an extremely low risk of dying from PCa within seven years. In patients with a baseline PSA level between 8 and 50 ng/ml, PSA doubling time was a prognostic factor of dying from PCa. Immediate hormone-ablation therapy is indicated when PSA doubling time is less than twelve months. The authors conclude that in patients with a baseline PSA level of less than 50 ng/ml, the first two years after diagnosis should be used to accurately determine the PSA doubling time, so that the decision to use hormone-ablation therapy can be made on the basis of the PSA doubling time [736].

The data from this evaluation suggest the following recommended course of action in terms of stratification: patients with a baseline PSA value of more than 50 ng/ml and/or a PSA doubling time of less than twelve months benefit from immediate hormone-ablation therapy. Patients with a baseline PSA level below 50 ng/ml and a PSA doubling time greater than twelve months have a significantly lower risk of dying from prostate cancer, and therefore hormone-ablation therapy can be delayed [736].

Re: Statement 6.76

Patients with low-risk tumors, i.e., cT1c-cT2a, N0, M0, Gleason score 6, and PSA <10 ng/ml are excluded from the recommendation. The EORTC trial 30891 [735] randomized patients refusing curative therapy for localized prostate cancer. The immediate hormone-deprivation therapy group showed no survival benefit over the delayed hormone-deprivation therapy group in either cancer-specific or overall survival. In the delayed-treatment group, more than half received therapy at a median of 2.8 years; however, 44% never needed hormone-deprivation therapy. There was a significant reduction in the likelihood of metastases occurring over 10 years for the immediately treated group. In a subgroup analysis of the study published as a conference abstract, EORTC trial 30891 showed a clear advantage for immediate initiation of hormone-deprivation therapy in patients younger than 70 years of age only when primary PSA exceeded 20 ng/ml, and in patients older than 70 years only when PSA exceeded 50 ng/ml [738].

In localized prostate cancer, the duration of treatment until natural or cancer-related death is potentially very long. The likelihood of side effects (flushing, osteoporosis, truncal weight gain, muscle wasting, etc.) is high (see Table 13). This high probability of side effects must be carefully weighed up against the benefits described above.

Re: Recommendation 6.77

This recommendation cites agents that have been used for hormone-ablation therapy in locally-advanced PCa: The meta-analysis by Wilt 2001 [734] [739] includes studies on orchidectomy and on LH-RH agonists. In addition, in the VACURG studies [728] estrogens and DES were also used. Iversen 2006 treated patients with bicalutamide: Studer 2006 [729] also uses an LH-RH agonist or orchidectomy. The use of GnRH blockers is justified on the basis an inverse argument as they are equally effective at lowering testosterone levels as LH-RH agonists. The GnRH blockers Abarelix and Degarelix are approved for the indication of hormone-ablation therapy for advanced PCa.