13. Attachments – Prostate Cancer

Version 6.2 · October 2021 · AWMF 043/022OL
Leitlinienprogramm Onkologie · Deutsche Krebsgesellschaft · Deutsche Krebshilfe · AWMF

13.1 Key questions and author groups

Table 23: Key questions and author groups

Key question(s)	Author(s)	Year, Update
Locally-confined prostate carcinoma
Significance of brachytherapy	Blana, Böhmer, Borkowetz, Cash, Ehrmann, Franiel, Ganzer, Hakenberg, Henkel, Höcht, Kristiansen, Machtens, Niehoff, Penzkofer, Pinkawa, Radtke, Roth, Schlemmer, Schostak	2021, 5th Update
Significance of focal therapies	Blana, Böhmer, Borkowetz, Cash, Ehrmann, Franiel, Ganzer, Hakenberg, Henkel, Höcht, Kristiansen, Machtens, Niehoff, Penzkofer, Pinkawa, Radtke, Roth, Schlemmer, Schostak	2021, 5th update
Follow-up for patients under Active Surveillance	Hadaschik, Hakenberg, Steuber	2018, 4th update
Radiotherapy with IG-IMRT	Fröhner, Graefen, Hakenberg, Höcht, Sedlmayer, Wiegel, Wirth	2018, 4th update
Significance of proton therapy	Hakenberg, Müller-Lisse, Ohlmann, Vögeli, Wenz, Wiegel	2018, 4th update
Significance of whole-gland HIFU therapy and focal therapy	Böhmer, Fornara, Grimm, Lümmen, Müller-Lisse, Schostak, Schrader, Stöckle, von Amsberg	2018, 4th update
Significance of concomitant hormonal ablation therapy	Flentje, Grimm, Heidenreich, Höcht, Semjonow, Wirth, Wörmann	2018, 4th update
Significance of hypofractionation	Böhmer, Fornara, Fröhner, Graefen, Wenz, Wiegel	2016, 3rd update
Treatment of low-risk carcinoma	Fröhner, Börgermann	2014, 2nd update
Significance of comorbidity classifications as aid instruments for therapy-related decisions in early prostate carcinoma	Fröhner, Wirth, Wedding	2014, 2nd update
Significance of Watchful Waiting and Active Surveillance.	Weißbach, Graefen, Burchardt, Grimm, Fiebrandt, Fornara, Heidenreich, Rübben, Wagner, Wernert, Wiegel	Initial version 2009 and/or 1st update 2011
Significance of radical prostatectomy: Which patients are best suited for radical prostatectomy?	Wirth, Grimm, Enders, Fröhner, Thomas, Thüroff , Steuber, Heidenreich, Vögeli	Initial version 2009 and/or 1st update 2011
Significance of percutaneous radiotherapy: Which patients are suited for radiotherapy?	Böhmer, Hölscher, Machtens, Wenz, Wiegel, Höcht, Sedlmayer, Martin, Moser, Hinkelbein, Zacharias.	Initial version 2009 and/or 1st update 2011
Significance of brachytherapy/seed treatment: Which patients are suited for LDR brachytherapy?	Borchers, Machtens, Jakse, Alberti, Henkel, Schmitz-Dräger, Zacharias	Initial version 2009 and/or 1st update 2011
Significance of brachytherapy/seed treatment: Which patients are suited for HDR brachytherapy?	Böhmer, Alberti, Deger, Galalae, Goldner, Martin, Wiegel	Initial version 2009 and/or 1st update 2011
Significance of hormonal ablation therapy: Which patients are suited for primary hormonal ablation therapy?	Ebert, Lümmen	Initial version 2009 and/or 1st update 2011
Significance of lymphadenectomy: When is a lymphadenectomy sensible?	Thüroff, Thomas, Burchard, Heidenreich, Küfer, Wiegel	Initial version 2009 and/or 1st update 2011
Significance of adjuvant and neoadjuvant therapy	Miller, Borchers, Fichtner, Rübben, Schostak, Wiegel	Initial version 2009 and/or 1st update 2011
Significance of other interventional procedures	Jocham, Jakse, Tedsen, Doehn, Schmitz-Dräger, Blana, Schostak, Enders	Initial version 2009 and/or 1st update 2011
Locally-advanced prostate carcinoma
Significance of brachytherapy	Blana, Böhmer, Borkowetz, Cash, Ehrmann, Franiel, Ganzer, Hakenberg, Henkel, Höcht, Kristiansen, Machtens, Niehoff, Penzkofer, Pinkawa, Radtke, Roth, Schlemmer, Schostak	2021, 5th update
Significance of focal therapies	Blana, Böhmer, Borkowetz, Cash, Ehrmann, Franiel, Ganzer, Hakenberg, Henkel, Höcht, Kristiansen, Machtens, Niehoff, Penzkofer, Pinkawa, Radtke, Roth, Schlemmer, Schostak	2021, 5th update
Significance of adjuvant radiotherapy	Aebersold, Asbach, Fröhner, Graefen, Hammerer, Paradies, Siemer, Wiegel, Wirth, Zips	2021, 5th update
Radiotherapy with IG-IMRT	Fröhner, Graefen, Hakenberg, Höcht, Sedlmayer, Wiegel, Wirth	2018, 4th update
Significance of proton therapy	Hakenberg, Müller-Lisse, Ohlmann, Vögeli, Wenz, Wiegel	2018, 4th update
Significance of HIFU therapy and other interventional procedures	Böhmer, Fornara, Grimm, Lümmen, Müller-Lisse, Schostak, Schrader, Stöckle, von Amsberg	2018, 4th update
Significance of pelvine lymphatic drainage irradiation	Fröhner, Ganswindt, Graefen, Kotzerke, Lein, Martin, Zips	2018, 4th update
Significance of concomitant hormonal ablation therapy	Flentje, Grimm, Heidenreich, Höcht, Semjonow, Wirth, Wörmann	2018, 4th update
Is Watchful Waiting reasonable in category T3 or T4?	Weißbach, Heidenreich	Initial version 2009 and/or 1st update 2011
Which patients in clinical category T3 shall be offered surgical treatment? Are there indications for surgical treatment in category T4?	Wirth, Grimm, Fröhner, Thomas, Thüroff, Steuber, Heidenreich, Vögeli, Enders	Initial version 2009 and/or 1st update 2011
Should patients in category cT3 receive a different RT than patients in category cT1/2? Can RT or BT in category cT4 have curative intent? Should the cN status determined clinically and presurgically influence therapy decisions?	Böhmer, Hölscher, Machtens, Wenz, Wiegel, Höcht, Sedlmayer, Martin, Moser, Hinkelbein, Zacharias.	Initial version 2009 and/or 1st update 2011
Can HDR treatment in category cT4 have curative intent?	Böhmer, Alberti, Deger, Galalae, Goldner, Martin, Wiegel	Initial version 2009 and/or 1st update 2011
Is there an indication for primary hormonal ablation therapy in nonmetastatic PCa?	Ebert, Lümmen	Initial version 2009 and/or 1st update 2011
Should patients in the clinical categories T3 and T4 who receive a local treatment with curative intent (RPE, RT, BT) undergo lymphadenectomy?	Thüroff, Thomas, Burchard, Heidenreich, Küfer, Wiegel	Initial version 2009 and/or 1st update 2011
Should patients in the clinical categories T3 and T4 who receive a local treatment with curative intent (RPE, RT, BT) receive adjuvant and/or neoadjuvant treatment?	Miller, Borchers, Fichtner, Rübben, Schostak, Wiegel	Initial version 2009 and/or 1st update 2011
What are the goals for the use of HIFU, cryothermal/hyperthermal ablation in categories T3/4?	Jakse, Jocham, Doehn, Tedsen, Schmitz-Dräger, Blana, Schostak, Fiebrandt	Initial version 2009 and/or 1st update 2011
Lymph node-positive PCa: Which treatment?	Wolff, Hinkelbein, Höcht, Thomas, Thüroff,	Initial version 2009 and/or 1st update 2011
Recurrent or metastatic prostate carcinoma
Treatment of PSA recurrence	Aebersold, Asbach, Fröhner, Graefen, Hammerer, Paradies, Siemer, Wiegel, Wirth, Zips	2021, 5th update
Treatment with apalutamid, darolutamid, enzalutamid, abirateron and olaparib	Baumann, Goebell, Grimm, Hoffmann, Kaiser, Müller, Ohlmann, Semjonow, von Amsberg, Wolff, Wörmann	2021, 5th update
Treatment with radium-223	Beckers, Bolenz, Flentje, Karger, Krause, Rahbar, Schimmöller, Schmidt, Schmidt-Hegemann, Steuber, Gerlach, Volkmer, Wawroschek, Wedding, Zastrow	2021, 5th update
Treatment with lutetium-177-PSMA	Beckers, Bolenz, Flentje, Karger, Krause, Rahbar, Schimmöller, Schmidt, Schmidt-Hegemann, Steuber, Gerlach, Volkmer, Wawroschek, Wedding, Zastrow	2021, 5th update
Local therapy for metastatic prostate carcinoma until prostatectomy, radiotherapy and metastasis-centered treatment	Aebersold, Afshar-Oromieh, Carl, Eiber, Fröhner, Heidenreich, Otto, Pummer, Sedlmayer, Stenzl, Wagner, Wiedemann, Wörmann, Zastrow	2021, 5th update
Early hormone-chemotherapy	Heidenreich, Miller, Ohlmann, von Amsberg, Wörmann, Zastrow	2018, 4th update
Treatment of metastatic PCa: first-line therapy	Heidenreich, Miller, Ohlmann, von Amsberg, Wörmann, Zastrow	2018, 4th update
Treatment of metastatic PCa: second-line therapy	Heidenreich, Miller, Ohlmann, von Amsberg, Wörmann, Zastrow	2018, 4th update
Treatment of metastatic PCa: Attempt to treat with Lu177-PSMA	Heidenreich, Miller, Ohlmann, von Amsberg, Wörmann, Zastrow	2018, 4th update
Treatment of metastatic PCa: Preventing complications in bone metastases	Heidenreich, Miller, Ohlmann, von Amsberg, Wörmann, Zastrow	2018, 4th update
Significance of HIFU salvage treatment	Böhmer, Fornara, Grimm, Lümmen, Müller-Lisse, Schostak, Schrader, Stöckle, von Amsberg	2018, 4th update
Early hormone-chemotherapie	Heidenreich, Miller, Ohlmann, von Amsberg, Wörmann, Zastrow	2016, 3rd update
Geriatric assessment for patients prior to chemotherapy	Wedding, Weißbach	2014, 2nd update
Systemic therapy (incl. combination therapy) of castration-resistant prostate carcinoma	Wörmann, Zastrow, Palmedo, Miller, Wirth	2014, 2nd update
Treatment of osseous metastases	Wörmann, Zastrow, Palmedo, Miller, Heidenreich, Wirth	2014, 2nd update
Treatment of metastatic PCa: Treatment of symptomatic/asymptomatic bone metastases	Rohde, Albrecht, Palmedo, Wörmann, Lümmen, Luboldt, Lein, Wolff	Initial version 2009 and/or 1st update 2011
Treatment of metastatic PCa: Supportive therapy: Measures against burdensome symptoms (tumor-/therapy-related)	Wörmann, Albrecht, Enders, Schmitz-Dräger	Initial version 2009 and/or 1st update 2011
Treatment of metastatic PCa: Treatment of urinary obstruction in castration-resistant PCa	Weißbach, Heidenreich	Initial version 2009 and/or 1st update 2011
Treatment of metastatic PCa: Imaging in the course of metastatic PCa (added in diagnosis of recurrence/staging)	Luboldt, Beyersdorff, Palmedo	Initial version 2009 and/or 1st update 2011
Characteristics of tumors in recurrence: Treatment of PSA recurrence after RPE (local/systemic)	Wiegel, Alberti, Börgermann, Hakenberg, Heidenreich, Sedlmayer	Initial version 2009 and/or 1st update 2011
Characteristics of tumors in recurrence: Treatment of PSA recurrence after radiotherapy	Hakenberg, Heidenreich, Alberti, Börgermann, Sedlmayer	Initial version 2009 and/or 1st update 2011
Treatment of castration-resistant PCa: Which drugs to use in the case of castration-resistant PCa?	Wirth, Fröhner, Grimm, Miller, Pummer, Schulz, Wörmann, Wolff, Hakenberg, Heidenreich, Rohde	Initial version 2009 and/or 1st update 2011
When is maximum androgen deprivation superior to regular androgen deprivation (orchidectomy, LH-RH analog)?	Rhode, Grimm, Lümmen, Wolff	Initial version 2009 and/or 1st update 2011
Significance of intermittent androgen blockade: Intermittent androgen blockade: Standard treatment?	Grimm, Wolff, Hammerer, Lümmen, Rohde	Initial version 2009 and/or 1st update 2011
Diagnosis/Staging
MRI-guided biopsy	Albers, Beyersdorff, Burchardt, Enders, Gratzke, Hadaschik, Hartmann, Holdenrieder, Kristiansen, Loch, Lümmen, Schlemmer	2021, 5th update
PSMA-PET (CT)	Grimm	2021, 5th update
Significance of MRI in primary diagnosis (initial and rebiopsy)	Albers, Beyersdorff, Borkowetz, Ganswindt, Loch, Müller-Lisse, Pelzer, Schlemmer	2018, 4th update
Significance of MRI ultrasound fusion biopsy	Albers, Borkowetz, Ganswindt, Loch, Mueller-Lisse, Pelzer, Schlemmer	2016, 3rd update
Significance of PSMA-PET imaging	Hadaschik, Hakenberg, Kotzerke, Krause, Sedlmayer	2016, 3rd update
Significance of PET/CT or PET/MRI for PSA recurrence after radical prostatectomy or radiotherapy	Kotzerke, Miller, Wiegel	2014, 2nd update
Significance of DNA cytometry	Kristiansen, Weißbach, Dietz, Böcking, Wernert	2014, 2nd update
Significance of additional immunohistochemical examinations	Kristiansen, Wernert, Weißbach	2014, 2nd update
Diagnosis, staging, findings report: Staging, spread diagnosis	Miller, Beyersdorff, Enders, Fornara, Göckel-Beining, Graefen, Krause, Müller-Lisse, Palmedo, Schrader	Initial version 2009 and/or 1st update 2011
Diagnosis, staging, findings report: Pathomorphological examination	Wernert, Jakse, Kahl, Ludoldt, Wetterauer	Initial version 2009 and/or 1st update 2011
Risk factors/prevention/early detection
Early detection	Bolenz, Burger, Carl, Ghadjar, Hakenberg, Lümmen, Kötter, Micke, Schlemmer, Uebel	2021, 5th update
Testosterone substitution as a potential risk facktor	Böhmer, Karger, Lümmen, Machtens, Schmitz-Dräger, Wiedemann	2018, 4th update
Risk-adapted time intervals, onset age limit for early dection	Rübben, Börgermann, Egidi	2014, 2nd update
Risk factors/prevention, including nutrition: Prevention of PCa.	Schmitz-Dräger, Fiebrandt, Lümmen	Initial version 2009 and/or 1st update 2011
Prevention, including nutrition: Significance of nutrition in manifest PCa	Schmitz-Dräger, Fiebrandt, Lümmen	Initial version 2009 and/or 1st update 2011
Significance of early detection/screening: Is a PCa screening sensible?	Rübben, Börgermann, Dubben, Fiebrandt, Fornara, Loertzer, Luboldt, Schulz, Semjonow, Stöckle, Vögeli, Weißbach,	Initial version 2009 and/or 1st update 2011
Significance of early detection/screening: When is a PCa insignificant?	Fornara, Rübben, Wagner, Wernert, Wiegel	Initial version 2009 and/or 1st update 2011
Testosterone substitution in the context of PCa	Ackermann, Behre, Nieschlag, Volkmer, Wetterauer	Initial version 2009 and/or 1st update 2011
Significance of a biopsy: Biopsy – when and how?	Rübben, Börgermann, Fornara, Hammerer, Loertzer, Luboldt, Schulz, Semjonow	Initial version 2009 and/or 1st update 2011
Rehabilitation/Aftercare
Significance of physiotherapy for incontinence and erectile dysfunction after treatment with curative intent	Ghadjar, Loertzer, Luboldt, Otto, Uebel, Wedding	2018, 4th update
Significance of exercise therapy after hormone deprivation treatment	Ghadjar, Loertzer, Luboldt, Otto, Uebel, Wedding	2018, 4th update
Significance of rehabilitation after therapy with curative intent	Jünemann, Ebermayer, Kaufmann, Otto, Weißbach	Initial version 2009 and/or 1st update 2011
Significance of follow-up/aftercare parameters: Follow-up: When and how?	Graefen, Alberti	Initial version 2009 and/or 1st update 2011
Tumor recurrence: Definition and diagnosis	Sedlmayer, Alberti, Börgermann, Hakenberg, Palmedo	Initial version 2009 and/or 1st update 2011
Significance of quality of life: Psychosocial aspects and quality of life for PCa	Jocham, Tedsen, Doehn, Koller, Rohde, representatives of self-help groups	Initial version 2009 and/or 1st update 2011

13.2 Changes after the current update

Table 24: Changes in the recommendations after update 6 of 2021

Version 5 (2018)	Version 6 (2021)
Chapter 4 Early detection	Chapter 4 Early detection
Recommendation 4.1 Men who are at least 45 years of age and have an estimated life expectancy of more than 10 years should be informed about early detection options. This age limit can be lowered by 5 years in men with a heightened risk of prostate carcinoma. These men shall be educated on the benefits and risks of early detection measures, especially the significance of positive and negative test results, as well as further measures that may be required. Special vote of the DEGAM in respect to the role of general practicioners for Recommendation 4.1 Men who do not express the desire for a screening by PSA to their primary care physician shall not be actively approached about it. The men who ask for early detection of their own accord shall be informed about the advantages and disadvantages in an open-ended manner. The potential benefits as well as the risks (overdiagnosis and overtherapy) shall be presented in natural numbers and also graphically. Similarly, the significance of positive and negative test results shall be presented.	Recommendation 4.1 If there is a reason for providing information about early detection of prostate cancer, men shall be given open and unbiased advice about the advantages and disadvantages, in particular with regard to the significance of positive and negative test results, overdiagnosis, and any further measures that may be required.
Recommendation 4.2 Men who wish to have a screening examination after education shall be offered the determination of the PSA value as an examination method. In addition, a digital-rectal examination should be recommended.	Recommendation 4.2 Men who wish to have a screening examination after informed consent shall be offered testing to determinate their PSA value as an examination method. In addition, a digital-rectal examination can be performed.
Statement 4.3 For the early detection of prostate cancer, imaging techniques are not suitable as a primary examination.	Statement 4.3 (remained unchanged) For the early detection of prostate cancer, imaging techniques are not suitable as a primary examination.
Recommendation 4.4 An elevated PSA value shall be monitored taking into account influencing factors.	Recommendation 4.4 (remained unchanged) An elevated PSA value shall be monitored taking into account influencing factors.
Recommendation 4.5 For men who wish to continue PSA screening, the follow-up interval should be based on the patient's current PSA level and age, unless there is an indication for biopsy. Age group 45 years and older and a life expectancy > 10 years. • PSA < 1 ng/ml: interval every 4 years • PSA 1-2 ng/ml: interval every 2 years • PSA > 2 ng/ml: interval every year For men over 70 years of age and a PSA < 1ng/ml, further PSA-based screening is not recommended.	Recommendation 4.5 (remained unchanged) For men who wish to continue PSA screening, the follow-up interval should be based on the patient's current PSA level and age, unless there is an indication for biopsy. Age group 45 years and older and a life expectancy > 10 years. • PSA < 1 ng/ml: interval every 4 years • PSA 1-2 ng/ml: interval every 2 years • PSA > 2 ng/ml: interval every year For men over 70 years of age and a PSA < 1ng/ml, further PSA-based screening is not recommended.
Recommendation 4.6 In the context of screening, prostate biopsy shall be recommended if at least one of the following criteria is met: • Screening PSA level of ≥ 4 ng/ml at the initial screening consultation, taking into account influencing factors; • Result suspicious for carcinoma on digital-rectal examination; • Abnormal PSA increase (without change in the method used for determination).	Recommendation 4.6 (remained unchanged) In the context of screening, prostate biopsy shall be recommended if at least one of the following criteria is met: • Screening PSA level of ≥ 4 ng/ml at the initial screening consultation, taking into account influencing factors; • Result suspicious for carcinoma on digital-rectal examination; • Abnormal PSA increase (without change in the method used for determination).
Chapter 5 Diagnosis and Staging	Chapter 5 Diagnosis and Staging
Recommendation 5.13 MRI of the prostate shall be performed multiparametrically according to current quality standards. (For indication see 5.15 to 5.18.)	Recommendation 5.13 (editorial changes) MRI of the prostate shall be performed multiparametrically (mpMRI) according to current quality standards. (For indication see 5.15 to 5.18.)
Recommendation 5.14 a. The carcinoma-suspected foci described on prostate MRI shall be targeted for biopsy. b. In addition to the MRI-targeted biopsy, a systematic biopsy should be performed simultaneously	Recommendation 5.14 a. The foci which are suspicious for carcinoma as described on mpMRI shall be biopsied in a targeted manner. b. In addition to the mpMRI-targeted biopsy, a systematic biopsy should be performed as part of the initial biopsy.
Statement 5.15 The majority of study results on MRI-guided vs. systematic biopsy vs. a combination of both procedures in previously biopsy-naïve men indicate that MRI-guided biopsy detects significant cancers slightly more frequently (in the range of 10%) than systematic biopsy alone. However, significant cancers are missed in MRI and targeted biopsy, just as systematic biopsy fails to detect a relevant proportion (in the range of 20%). The combination of an MRI-guided targeted approach plus systematic biopsy achieves better detection rates than either method alone.	Statement 5.15 (editiorial changes) The majority of study results on mpMRI-guided vs. systematic biopsy vs. a combination of both procedures in previously biopsy-naïve men indicate that mpMRI-guided biopsy detects significant cancers slightly more frequently (in the range of 10%) than systematic biopsy alone. However, significant cancers are missed in mpMRI and targeted biopsy, just as systematic biopsy fails to detect a relevant proportion (in the range of 20%). The combination of an mpMRI-guided targeted approach plus systematic biopsy achieves better detection rates than either method alone.
Recommendation 5.16 a. MRI according to current quality standards can be used as part of primary diagnosis. However, it is not part of the diagnostic routine. b. An inconspicuous result on mpMRI (PI-RADS <3) carries a residual risk of significant tumors, such that a systematic biopsy should be offered in addition to PSA-based monitoring.	Recommendation 5.16 a. mpMRI according to current quality standards should be used as part of primary diagnosis. b. A normal result on mpMRI (PI-RADS <3) carries a residual risk of significant tumors, such that a systematic biopsy should be offered in addition to PSA-based monitoring.
Recommendation 5.17 a. After negative systematic biopsy without prior MRI, if carcinoma is still suspected, imaging by MRI should be performed according to the applicable quality standards. b. After negative rebiopsy (MRI-guided plus systemic biopsy), no further invasive intervention should be performed if clinical parameters (DRE and PSA) remain unchanged. c. After negative rebiopsy (MRI-guided plus systemic biopsy), no further imaging procedure should be performed if clinical parameters (DRE and PSA) remain unchanged.	Recommendation 5.17 a. After negative systematic biopsy without prior mpMRI, if carcinoma is still suspected, imaging by mpMRI shall be performed according to the applicable quality standards. b. After negative rebiopsy, no further invasive intervention shall be performed if clinical parameters (DRE and PSA) remain unchanged.
Recommendation 5.18 a. Patients considering Active Surveillance as a treatment option shall be given an MRI that meets current quality standards prior to this being indicated. b. If suspicious areas (PI-RADS) are seen on MRI, they shall be targeted for biopsy.	Recommendation 5.18 a. Patients considering Active Surveillance shall be given an mpMRI that meets current quality standards prior to this being indicated. b. If suspicious areas (PI-RADS 3-5) are seen on mpMRI, they shall be targeted for biopsy.
Recommendation 5.25	Recommendation/Statement 5.25 a.PSMA-PET has a higher accuracy (precision) for detecting prostate cancer metastases than the combination of computed tomography and bone scintigraphy. b. PSMA-PET/CT can be used in high-risk prostate cancer (Gleason score 8-10 or T category cT3/cT4 or PSA≥20ng/ml) for diagnosis of metastasis.
Chapter 6.3 Local treatments for localized prostate carcinoma	Chapter 6.3 Local treatments for localized prostate carcinoma
Statement 6.25 Interstitial LDR monotherapy is a primary therapeutic option for the treatment of localized prostate cancer with a low-risk profile.	Statement 6.25 (remained unchanged) Interstitial LDR monotherapy is a primary therapeutic option for the treatment of localized prostate cancer with a low-risk profile.
There can still be no recommendation made regarding LDR brachytherapy in patients with localized prostate carcinoma of the intermediate-risk profile due to the heterogeneous state of the literature (see background text 6.26).	Statement removed
Recommendation 6.26 Patients with high-risk prostate cancer shall not receive LDR monotherapy.	Recommendation 6.26 (remained unchanged) Patients with high-risk prostate cancer shall not receive LDR monotherapy.
Recommendation 6.27 The combination of LDR brachytherapy with percutaneous radiotherapy and/or hormone ablative therapy for patients with high-risk prostate cancer shall be reserved for controlled trials.	Recommendation 6.27 a. For intermediate- or high-risk localized prostate cancer, primary combined percutaneous radiation plus LDR/HDR brachytherapy boost can be performed in conjunction with short-term or long-term androgen deprivation therapy (ADT). b. Patients shall be educated about the significant increase in late toxicity (≥ grade 3) associated with this form of therapy. c. Androgen deprivation therapy (ADT) shall be used when brachytherapy is used, analogously to the recommendations for percutaneous radiotherapy.
Recommendation 6.28 HDR brachytherapy, combined with percutaneous radiotherapy, is a primary treatment option for localized prostate cancer.	Recommendation 6.28 (remained unchanged) HDR brachytherapy, combined with percutaneous radiotherapy, is a primary treatment option for localized prostate cancer.
Statement 6.29 a. HDR brachytherapy, combined with percutaneous radiotherapy, is a primary treatment option for patients with intermediate and high-risk profile tumors. b. The value of additional hormone-ablation therapy has not been clarified.	Statement 6.29 (remained unchanged) a. HDR brachytherapy, combined with percutaneous radiotherapy, is a primary treatment option for patients with intermediate and high-risk profile tumors. b. The value of additional hormone-ablation therapy has not been clarified.
Recommendation 6.30 HDR monotherapy in patients with low-risk profile tumors shall be used exclusively in controlled trials.	Recommendation 6.30 (remained unchanged) HDR monotherapy in patients with low-risk profile tumors shall be used exclusively in controlled trials.
-	Statement 6.36 In focal therapy for localized prostate cancer, only part of the prostate is treated.
-	Statement 6.37 The goal of focal therapy for localized prostate cancer is the eradication of all significant tumors.
-	Recommendation 6.38 Patients with low-risk unilateral localized prostate cancer can be offered focal therapy if they decline both standard therapies and Active Surveillance (AS) and meet the following requirements: - Gleason Score 6 - PSA < 10 ng/ml - inconspicuous palpation - maximum 50 % positive biopsies only on one side in the systematic biopsy - diagnosis by mpMRI, fusion biopsy and systematic biopsy.
-	Recommendation 6.39 a. Patients considering focal therapy shall receive mpMRI, mpMRI fusion biopsy, and systematic biopsy. b. Alternatively, if MRI fusion biopsy is not feasible, a template-based biopsy can be performed.
-	Recommendation 6.40 a. Patient education on focal therapy shall include the fact that there is no evidence that the therapy is equivalent to standard therapies. b. In the event that salvage therapy is required, patient education about focal therapy shall include, in addition to what is described in recommendation a., reference to potentially worse functional and oncological outcomes of salvage therapy.
-	Recommendation 6.41 When following the Active Surveillance strategy, a targeted and a systematic biopsy shall be performed 6 to 12 months after focal therapy (treated area targeted and the remaining gland additionally biopsied systematically).
Recommendation 6.36 Hyperthermia alone should not be used in the primary therapy of localized prostate cancer. Recommendation 6.37 Whole-gland HIFU therapy is an experimental procedure in localized prostate cancer and should only be used in prospective studies. Recommendation 6.38 Focal therapies as treatment of a part of the prostate in localized prostate cancer have a highly experimental character and should only be used in the context of prospective studies. Recommendation 6.39 Cryotherapy is not an adequate treatment alternative in the primary therapy of localized prostate carcinoma. There are no study data to justify the use of this procedure in the primary therapy of localized PCa.	Statement 6.42 There are no comparative data available comparing the different technologies for focal therapy that would allow an assessment of efficacy, side effects, and safety parameters.
-	Statement 6.43 Focal vascular-targeted photodynamic therapy (VTP) using padeliporfin is the only focal technology for which results are available from a prospective randomized-controlled trial comparing focal therapy for low-risk prostate cancer with active surveillance.
-	Statement 6.44 There are insufficient data to assess the oncological efficacy and safety of focal high-intensity focused ultrasound ablation (HIFU).
-	Statement 6.45 There are insufficient data to assess the oncological efficacy and safety of focal cryotherapy.
-	Statement 6.46 There are insufficient data to assess the oncological efficacy and safety of focal irreversible electroporation (IRE), particularly in terms of long-term outcomes.
-	Statement 6.47 There are insufficient data to assess the oncological efficacy and safety of focal laser ablation, focal brachytherapy, focal radiofrequency ablation (RFA), focal stereotactic radiation therapy (SBRT), focal microwave therapy, and focal transurethral ultrasound ablation.
Chapter 6.4 Local treatment of locally-advanced prostate carcinoma	Chapter 6.4 Local treatment of locally- advanced prostate carcinoma
Statement 6.49 In patients with locally advanced prostate cancer of clinical category cT3, HDR brachytherapy combined with percutaneous radiation is a therapeutic option. For tumors of clinical category cT4, HDR brachytherapy is not indicated. The same criteria apply for additional hormone ablative therapy as for combined hormone radiotherapy alone.	Recommendation 6.57 In patients with locally-advanced prostate carcinoma of clinical category cT3, HDR brachytherapy combined with percutaneous radiation is a treatment option. In tumors of clinical category cT4, HDR brachytherapy is not indicated. The same criteria apply for additional hormone-ablation therapy as for combined hormone radiotherapy alone.
-	Recommendation 6.60 Patients with locally-advanced prostate cancer shall not receive focal therapy – with any technology.
Statement 6.55 Adjuvant percutaneous radiotherapy is the term used for radiotherapy following radical prostatectomy after the defined PSA zero range has been reached. (For treatment in the case of PSA levels persisting postoperatively, see chapter 7.2. For definition of PSA progression, see chapter 7.1).	Statement 6.61 (remained unchanged) Adjuvant percutaneous radiotherapy is the term used for radiotherapy following radical prostatectomy after the defined PSA zero range has been reached. (For treatment in the case of PSA levels persisting postoperatively, see chapter 7.2. For definition of PSA progression, see chapter 7.1).
Recommendation 6.56 a. Patients with pT3pN0 tumors with positive resection margins should be offered adjuvant radiotherapy as an option with informed benefit and risk. b. Patients with pT3 tumors and negative resection margins but other risk factors such as seminal vesicle infiltration should be offered adjuvant radiotherapy as an option with explanation of benefits and risks, with a lower expected effect than with positive resection margins. c. Patients with pT2 tumors with positive resection margins may be offered adjuvant radiotherapy with explanation of the benefits and risks. d. For each of the three groups (a-c), the alternative option of percutaneous radiotherapy for PSA rise from the defined zero range should be mentioned during the adjuvant radiotherapy education (see Chapter 7.2 for treatment of PSA recurrence).	Recommendation 6.62 The indication for adjuvant radiotherapy is limited to the following high-risk groups: a. Patients with high-risk locally-advanced prostate carcinoma (pN0) and the following factors should be offered adjuvant radiotherapy as an option with informed benefit and risk: pT3/pT4+R1 (positive cut margin) + Gleason score 8-10 (ISUP 4-5). b. Patients with locally advanced prostate cancer (pN0) at increased risk and the following factors can be offered adjuvant radiotherapy as an option with informed benefit and risk: pT3/pT4+R0 (negative cut margin) + Gleason score 8-10 (ISUP 4-5). c. Patients with localized prostate carcinoma (pN0) and the following factors can be offered adjuvant radiotherapy as an option with explanation of benefits and risks: R1 (multifocal positive incisional margin) + Gleason score 8-10 + pT2. d. For each of the three groups (a-c), the alternative option of percutaneous radiotherapy for a rise in PSA from the defined zero range shall be mentioned as part of patient education on adjuvant radiotherapy (see Section 7.2 for treatment of PSA recurrence).
Chapter 7.2 Therapy of PSA recurrence	Chapter 7.2 Therapy of PSA recurrence
Statement 7.8 In patients with PSA recurrence and favorable prognostic criteria (see background information), wait-and-see is an option.	Statement 7.8 In patients with PSA recurrence and favorable prognostic criteria (PSA doubling time of > 12 months, Gleason score < 8 (ISUP <4)), wait-and-see is an option.
Recommendation 7.9 Percutaneous salvage radiotherapy (SRT) (min. 66 Gy) should be offered as a treatment option following radical prostatectomy for a PSA rise from the zero range in the pN0/NX category.	Recommendation 7.9 Percutaneous salvage radiotherapy (SRT) (min. 66 Gy) shall be offered as a treatment option following radical prostatectomy for a PSA rise from the zero range in the pN0/NX category.
-	Recommendation 7.10 Patients at high risk of progression (PSA before SRT > 0.7 ng/ml) shall be offered androgen deprivation therapy (ADT) or bicalutamide in addition to percutaneous salvage radiotherapy (SRT).
-	Recommendation 7.11 Percutaneous salvage radiotherapy (SRT) (min. 66 Gy) shall be offered in combination with androgen deprivation therapy (ADT) as a treatment option after radical prostatectomy for a PSA rise from the zero range and unfavorable prognostic criteria (PSA doubling time < 12 months, Gleason 8-10 (ISUP 4-5)) in the pN0/NX category.
-	Recommendation 7.12 If androgen deprivation therapy (ADT) is added to percutaneous radiotherapy (SRT), the duration of ADT can be based on the risk of progression (high risk of progression: 24 months; or increased risk of progression: 6 months).
Recommendation 7.10 a. Salvage radiotherapy shall be started as early as possible (PSA before SRT). b. With initial stage pN0 and early start to radiotherapy, lymphatic drainage pathways should not be irradiated.	Recommendation 7.13 (remained unchanged) a. Salvage radiotherapy shall be started as early as possible (PSA before SRT). b. With initial stage pN0 and early start to radiotherapy, lymphatic drainage pathways should not be irradiated.
Recommendation 7.11 Treatment of persistent PSA level (above the defined zero range) after radical prostatectomy can be performed according to the above principles of treatment of PSA recurrence.	Recommendation 7.14 Treatment of persistent PSA levels (above the defined zero range) following radical prostatectomy should follow the above principles of treatment for PSA recurrence.
Chapter 7.3 Treatment of hormone-sensitive metastatic prostate carcinoma (mHSPC)	Chapter 7.3 Treatment of hormone-sensitive metastatic prostate carcinoma (mHSPC)
Statement 7.17 The options of combined hormone therapy with docetaxel or with abiraterone (plus prednisone/prednisolone) have fundamentally changed the first-line treatment of metastatic (M1), hormone-sensitive prostate cancer at initial diagnosis.	Statement removed
-	Recommendation 7.20 Patients with metastatic hormone-sensitive prostate cancer (mHSPC) shall be classified as high and low-volume as well as high and low-risk.
Recommendation 7.18 Part of the information about sole androgen deprivation or combination therapy shall be the following points in particular: -the palliative nature of the therapy; -impact on quality of life; -the adverse effects.	Recommendation 7.21 (editorial changes) Part of the patient education about androgen deprivation alone or combination therapy shall include the following points in particular: •the palliative nature of the therapy; •impact on quality of life; •the adverse effects.
Recommendation 7.19 Patients in good general health (ECOG 0-1) with metastatic (M1), hormone-sensitive prostate cancer should be recommended chemotherapy with docetaxel or supplemental antihormonal therapy with abiraterone (plus prednisone/prednisolone) in addition to androgen deprivation.	Recommendation 7.22 a. Patients in good general health (ECOG 0-1) with metastatic (M1), hormone-sensitive, prostate cancer (mHSPC) shall be offered hormone therapy with apalutamide in addition to androgen deprivation. b. Patients in good general health (ECOG 0-1) with metastatic (M1), hormone-sensitive, prostate carcinoma (mHSPC) shall be offered hormone therapy with enzalutamide in addition to androgen deprivation. c. Patients in good general condition (ECOG 0-1) with newly-diagnosed (de novo), metastatic (M1), hormone-sensitive, high-risk prostate cancer (mHSPC) shall be offered hormone therapy with abiraterone (plus prednisone/prednisolone) in addition to androgen deprivation. d. Patients in good general condition (ECOG 0-1) with metastatic (M1), hormone-sensitive, high-volume prostate carcinoma (mHSPC) shall be offered chemotherapy with docetaxel in addition to androgen deprivation, with education about the higher toxicity compared with new hormonal agents. e. Patients in good general health (ECOG 0-1) with metastatic (M1), hormone-sensitive, low-volume prostate cancer (mHSPC) can be offered chemotherapy with docetaxel in addition to androgen deprivation.
Statement/Recommendation 7.20 It is currently unclear which patient groups will benefit more from which combination therapy The therapy decision should be made depending on patient preferences, side effects and concomitant diseases.	Recommendation 7.23 The therapeutic decision should be made depending on patient preferences, side effects and concomitant diseases.
Recommendation 7.21 a. If the patient chooses combined treatment of chemotherapy and androgen deprivation, docetaxel should be started within 4 months of the start of androgen deprivation. 6 cycles every three weeks at a dosage of 75mg/m² should be given. b. If the patient chooses combined treatment of androgen deprivation and abiraterone, abiraterone administration should begin within 3 months of the start of androgen deprivation. Therapy should be given at a dosage of 1000 mg/day in combination with prednisone or prednisolone (5 mg/day). c. Reasons for discontinuation should be: patient request, progression, or intolerable side effects.	Recommendation 7.24 a. If combined treatment of androgen deprivation and apalutamide is decided upon, apalutamide administration shall begin within 3 months of initiation of androgen deprivation. Therapy should be given at a dose of 240 mg/day. b. If combined treatment of androgen deprivation and enzalutamide is decided upon, enzalutamide administration shall begin within 3 months of the start of androgen deprivation. Therapy should be given at a dose of 160 mg/day. c. If combined treatment of androgen deprivation and abiraterone is chosen, abiraterone administration shall begin within 3 months of initiation of androgen deprivation. Therapy shall be given at a dose of 1000 mg/day in combination with prednisone or prednisolone (5 mg/day). d. If combined treatment of chemotherapy and androgen deprivation is decided, docetaxel administration shall begin within 4 months of the start of androgen deprivation. 6 cycles every three weeks at a dose of 75mg/m² shall be given. e. Reasons for discontinuation of therapy shall include: patient request, progression, or intolerable side effects.
Recommendation 7.22 a. Patients who are not eligible for combination treatment shall be recommended for androgen deprivation. b. Androgen deprivation can be performed with medication or surgery. c. Drug androgen deprivation can be given as monotherapy or as maximal androgen blockade. d. Androgen deprivation should be performed continuously if the PSA level does not fall below 4 ng/mL after 7 months at the latest. e. If the PSA level falls below 4 ng/mL, intermittent hormone therapy may be offered as an alternative after detailed explanation.	Recommendation 7.25 a. Patients who are not eligible for combination treatment shall be recommended for androgen deprivation. b. Androgen deprivation can be performed by medication or surgery. c. Androgen deprivation should be performed continuously if the PSA level does not fall below 4 ng/mL after at least 7 months. d. If the PSA level drops below 4 ng/mL, intermittent hormone therapy can be offered as an alternative after detailed patient education is provided.
7.4. Treatment of androgen-independent or castration-resistant prostate cancer (CRPC)	7.4. Treatment of androgen-independent or castration-resistant prostate cancer (CRPC)
Recommendation 7.23 Patients with castration-resistant prostate cancer shall be provided with information about the following: • A cure cannot be achieved. • Various options are available for further treatment.	Recommendation 7.26 (remained unchanged) Patients with castration-resistant prostate cancer shall be provided with information about the following: • A cure cannot be achieved. • Various options are available for further treatment.
Recommendation 7.24 In patients with symptomatic progressive disease undergoing castration with medication, therapeutic options and the therapeutic approach should be discussed and determined on an interdisciplinary basis.	Recommendation 7.27 (remained unchanged) In patients with symptomatic progressive disease undergoing castration with medication, therapeutic options and the therapeutic approach should be discussed and determined on an interdisciplinary basis.
Recommendation 7.25 The following factors shall be considered when making a treatment decision: • symptoms • side effects of treatment options • patient preference • comorbidities, life expectancy, and quality of life • progression over time • localization of metastases and general tumor burden.	Recommendation 7.28 (remained unchanged) The following factors shall be considered when making a treatment decision: • symptoms • side effects of treatment options • patient preference • comorbidities, life expectancy, and quality of life • progression over time • localization of metastases and general tumor burden.
Statement 7.26 Suitability for treatment with chemotherapy is not a clearly defined variable. Therefore, there is a lack of threshold values above which suitability for treatment can be determined or otherwise.	Statement 7.29 (remained unchanged) Suitability for treatment with chemotherapy is not a clearly defined variable. Therefore, there is a lack of threshold values above which suitability for treatment can be determined or otherwise.
Statement 7.27 A geriatric assessment is useful for decision making before initiating tumor-specific therapy in multimorbid patients older than 70 years.	Statement 7.30 (remained unchanged) A geriatric assessment is useful for decision making before initiating tumor-specific therapy in multimorbid patients older than 70 years.
Recommendation 7.28 Serum testosterone levels shall be monitored in patients with progressive disease undergoing surgical or drug castration therapy.	Recommendation 7.31 (remained unchanged) Serum testosterone levels shall be monitored in patients with progressive disease undergoing surgical or drug castration therapy.
Recommendation 7.29 Patients with castration-resistant, asymptomatic, or mildly symptomatic progressive disease without imaging evidence of metastases shall be offered a wait-and-see approach while maintaining androgen deprivation.	Recommendation removed
-	Recommendation 7.32 Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and a high risk of metastasis (PSA doubling time of <10 months) shall be offered apalutamide, darolutamide, or enzalutamide (alphabetical order) in addition to androgen deprivation therapy (ADT).
-	Recommendation 7.33 The indication for intensified treatment according to 7.32 should take into account presumed life expectancy (based on age, among other factors) as well as potential adverse effects and quality of life.
Recommendation 7.30 Patients with metastatic, castration-resistant, asymptomatic or mildly-symptomatic and progressive disease who are taking an androgen deprivation treatment can be offered a change of treatment provided the benefits and side effects are explained to them. The specific conditions and side effects of the therapies should be taken into account.	Recommendation 7.34 (remained unchanged) Patients with metastatic, castration-resistant, asymptomatic or mildly-symptomatic and progressive disease who are taking an androgen deprivation treatment can be offered a change of treatment provided the benefits and side effects are explained to them. The specific conditions and side effects of the therapies should be taken into account.
Recommendation 7.31 When a patient with metastatic, castration-resistant, asymptomatic, or low-symptomatic and progressive disease has decided against a wait-and-see approach, opting to switch treatment, one of the following options shall be offered: (alphabetical order) · abiraterone (in combination with prednisone/prednisolone) · docetaxel · enzalutamide For differential therapy, see Recommendations 7.36 and 7.37.	Recommendation 7.35 (remained unchanged) When a patient with metastatic, castration-resistant, asymptomatic, or low-symptomatic and progressive disease has decided against a wait-and-see approach, opting to switch treatment, one of the following options shall be offered: (alphabetical order) · abiraterone (in combination with prednisone/prednisolone) · docetaxel · enzalutamide For differential therapy, see Recommendations 7.36 and 7.37.
Recommendation 7.32 Patients with metastatic, castration-resistant, asymptomatic, or low-symptomatic and progressive disease should be offered (in alphabetical order) - Abiraterone (in combination with prednisone / prednisolone) or - enzalutamide as first-line therapy.	Recommendation 7.36 (editorial changes) Patients with metastatic, castration-resistant, asymptomatic, or mildly-symptomatic and progressive disease should be offered (in alphapetical order): · abiraterone (in combination with prednisone/prednisolone); or · enzalutamide
Recommendation 7.33 Patients with metastatic, castration-resistant, asymptomatic, or mildly symptomatic and progressive disease may be offered docetaxel as first-line therapy.	Recommendation 7.37 (editorial changes) Patients with metastatic, castration-resistant, asymptomatic, or mildly-symptomatic and progressive disease can be offered docetaxel.
Recommendation 7.34 Patients with metastatic, castration-resistant, symptomatic, progressive disease and good general condition should be treated with a systemic systemic therapy as first-line therapy, if necessary in combination with symptomatic with symptom-based and supportive therapy, as first-line therapy. For differential therapy, see recommendations 7.35, 7.36, 7.37.	Recommendation 7.38 (editorial changes) Patients with metastatic, castration-resistant, symptomatic progressive disease who are in a good general condition shall be offered systemic therapy, if necessary in combination with symptom-related and supportive therapy. For differential therapy, see Recommendations 7.39, 7.40, 7.41.
Recommendation 7.35 Patients with metastatic, castration-resistant, symptomatic, and progressive disease may be offered docetaxel as first-line therapy in two- or three-week dosing regimens.	Recommendation 7.39 (editorial changes) Patients with metastatic, castration-resistant, symptomatic, and progressive disease can be offered docetaxel in two or three-week dosing regimens.
Recommendation 7.36 Patients with metastatic, castration-resistant, symptomatic, and progressive disease can be offered (in alphabetical order) • abiraterone (in combination with prednisone/prednisolone) or • enzalutamide as first-line therapy. Patients should be informed that only patients with low symptomatic disease were treated in the pivotal study.	Recommendation 7.40 (editorial changes) Patients with metastatic, castration-resistant, symptomatic, and progressive disease can be offered: (in alphabetical order) • abiraterone (in combination with prednisone/prednisolone); or • enzalutamide Patients shall be informed that only patients with low symptomatic disease were treated in the pivotal study.
Recommendation 7.37 Patients with castration-resistant, symptomatic, progressive disease with osseous metastases without evidence of extra-osseous distant metastases may be offered radium-223 as first-line therapy.	Recommendation removed
Recommendation 7.38 Patients with castration-resistant, symptomatic, progressive disease and reduced general condition (ECOG ≥ 2, Karnofsky index < 70) shall be offered symptom-based therapy.	Recommendation 7.41 (remained unchanged) Patients with castration-resistant, symptomatic, progressive disease and reduced general condition (ECOG ≥ 2, Karnofsky index < 70) shall be offered symptom-based therapy.
Recommendation 7.39 Patients with castration-resistant, progressive disease and reduced general condition (ECOG ≥ 2, Karnofsky index < 70) may additionally be offered one of the following treatment options as first-line therapy: (in alphabetical order) · abiraterone (in combination with prednisone / prednisolone); · chemotherapy, if the reduced general condition is primarily due to the metastatic prostate cancer; · enzalutamide; • radium-223 for osseous metastasis · steroids (dexamethasone, prednisolone, prednisone).	Recommendation 7.42 Patients with castration-resistant, progressive disease and reduced general condition (ECOG ≥ 2, Karnofsky index <70) can additionally be offered one of the following treatment options: (in alphabetical order) · abiraterone (in combination with prednisone / prednisolone); · chemotherapy, if the reduced general condition is primarily due to the metastatic prostate cancer; · enzalutamide; · steroids (dexamethasone, prednisolone, prednisone).
-	Recommendation 7.43 Patients with progression under a new hormonal agent (NHA) should be offered a change in therapeutic strategy.
-	Recommendation 7.44 Patients with progression after pre-therapy that included a new hormonal agent shall be offered testing for BRCA 1/2 mutations.
-	Recommendation 7.45 If a BRCA1/2 mutation is detected, therapy with olaparib shall be offered.
Recommendation 7.40 Patients with castration-resistant, progressive disease and good general health after chemotherapy with docetaxel shall be offered one of the following treatment options, in combination with symptom-based and supportive therapy if needed: (in alphabetical order) · Abiraterone (in combination with prednisone/prednisolone). · Cabazitaxel · Enzalutamide Radionuclide therapy with radium-223 for osseous metastasis. For differential therapy, see Recommendations 7.47 - 7.49.	Recommendation 7.46 Patients with castration-resistant, progressive disease and good general health after chemotherapy with docetaxel shall be offered one of the following treatment options, in combination with symptom-based and supportive therapy if needed: (in alphabetical order) · Abiraterone (in combination with prednisone/prednisolone). · Cabazitaxel · Enzalutamide For differential therapy, see Recommendations 7.47 - 7.49.
Recommendation 7.41 Patients with castration-resistant, progressive disease and good general condition after chemotherapy with docetaxel can be offered: (alphabetical order) • Abiraterone (in combination with prednisone/prednisolone) or • Enzalutamide A prolongation of survival was shown in the respective pivotal trial.	Recommendation 7.47 (remained unchanged) Patients with castration-resistant, progressive disease and good general condition after chemotherapy with docetaxel can be offered: (alphabetical order) • Abiraterone (in combination with prednisone/prednisolone) or • Enzalutamide A prolongation of survival was shown in the respective pivotal trial.
Recommendation 7.42 Cabazitaxel can be offered to patients with castration-resistant, progressive disease and good general condition after chemotherapy with docetaxel. A prolongation of survival was shown in the pivotal trial.	Recommendation 7.48 (remained unchanged) Cabazitaxel can be offered to patients with castration-resistant, progressive disease and good general condition after chemotherapy with docetaxel. A prolongation of survival was shown in the pivotal trial.
Recommendation 7.43 Patients with castration-resistant, progressive disease and good general condition after chemotherapy with docetaxel can be offered radium-223 for osseous metastases. Prolongation of survival was shown in the pivotal study.	Recommendation 7.49 a. Radium-223 can be offered to patients who have castration-resistant, progressive prostate cancer with symptomatic osseous metastases (without known visceral metastases) and good general health, and who have received at least two prior systemic therapy options in this indication, or for whom no other available systemic mCRPC therapy is suitable. b. Radium-223 shall not be used in combination with abiraterone and prednisone/prednisolone.
Recommendation 7.44 Patients with castration-resistant, progressive disease after chemotherapy with docetaxel and reduced general condition (ECOG ≥ 2, Karnofsky < 70) may be offered one of the following treatment options in addition to symptom-based therapy: (in alphabetical order) · Abiraterone (in combination with prednisone/prednisolone). · Chemotherapy if the reduced general condition is primarily due to metastatic prostate cancer · Enzalutamide • Radionuclide therapy with radium-223 for osseous metastasis · Steroids (dexamethasone, prednisolone, prednisone).	Recommendation 7.50 Patients with castration-resistant, progressive disease after chemotherapy with docetaxel and reduced general condition (ECOG ≥ 2, Karnofsky <70) can be offered one of the following treatment options, in addition to a symptom-based therapy: (in alphabetical order) · Abiraterone (in combination with prednisone/prednisolone). · Chemotherapy if the reduced general condition is primarily due to metastatic prostate cancer · Enzalutamide · Steroids (dexamethasone, prednisolone, prednisone).
Recommendation 7.45 For patients with castration-resistant, progressive disease in good general health, a trial of therapy with lutetium-177-PSMA can be offered based on the recommendation of an interdisciplinary tumor conference after other recommended therapeutic options (see Recommendation 7.46) are exhausted.	Recommendation 7.51 (remained unchanged) For patients with castration-resistant, progressive disease in good general health, a trial of therapy with lutetium-177-PSMA can be offered based on the recommendation of an interdisciplinary tumor conference after other recommended therapeutic options (see Recommendation 7.46) are exhausted.
Recommendation 7.46 Patients with castration-resistant, progressive disease and good general condition after first-line androgen receptor-targeted therapy can be offered sequential therapy using one of the other effective drugs (see Recommendation 7.40).	Recommendation 7.52 (editorial changes) Patients with castration-resistant, progressive disease and good general condition after androgen receptor-targeted therapy can be offered sequential therapy using one of the other effective drugs (see Recommendation 7.46).
-	Chapter 7.5 Local treatment for metastatic prostate cancer
-	Statement 7.53 Oligometastatic prostate cancer is defined as a tumor with a maximum of 4 bone metastases detectable on conventional imaging (skeletal scintigraphy and CT or MRI) without extraosseous visceral metastases.
-	Recommendation 7.54 a. Patients with newly diagnosed oligometastatic prostate cancer should receive percutaneous radiotherapy of the prostate in addition to systemic therapy. b. External beam radiotherapy (EBRT) should be administered in a hypofractionated manner, and the radiation dose should not exceed an equivalent dose of 72 Gy in 2 Gy standard fractionation.
-	Recommendation 7.55 Percutaneous radiotherapy of the prostate can be combined with extended systemic therapy (androgen deprivation (ADT) simultaneous, docetaxel sequential) in oligometastatic prostate cancer.
-	Recommendation/Statement 7.56 a. Radical prostatectomy is not adequately supported by evidence as a treatment option for oligometastatic prostate cancer. b. Radical prostatectomy can be offered for oligometastatic prostate cancer after discussion in an interdisciplinary tumor conference as part of multimodality therapy.
-	Recommendation/Statement 7.57 a. Metastasis-directed local ablative therapy for oligometastatic prostate cancer is not adequately supported by evidence, particularly with regard to oncological outcomes. b. Metastasis-directed local ablative therapy for oligometastatic prostate cancer can be used to delay androgen deprivation and/or tumor progression. c. External beam radiation therapy (EBRT) as ablative treatment should be hypofractionated, preferably as stereotactic radiation (SBRT).
Chapter 7.5 Therapy of bone metastases	Chapter 7.6 Therapy of bone metastases
Evidence-based Recommendation 7.49 Radionuclides can be used for pain management in multiple bone metastases at castration-resistant stage. Radium-223 therapy leads to prolonged survival in patients in good general condition (ECOG ≤ 2) without evidence of visceral metastases.	Recommendation 7.60 Radionuclides can be used for pain treatment in multiple bone metastases in the castration-resistant stage. Please refer to Recommendation 7.49 for the indication of radium-223.

Version 5 (2018)

Version 6 (2021)

Chapter 4 Early detection

Recommendation 4.1

Men who are at least 45 years of age and have an estimated life expectancy of more than 10 years should be informed about early detection options. This age limit can be lowered by 5 years in men with a heightened risk of prostate carcinoma.

These men shall be educated on the benefits and risks of early detection measures, especially the significance of positive and negative test results, as well as further measures that may be required.

Special vote of the DEGAM in respect to the role of general practicioners for Recommendation 4.1

Men who do not express the desire for a screening by PSA to their primary care physician shall not be actively approached about it.

The men who ask for early detection of their own accord shall be informed about the advantages and disadvantages in an open-ended manner. The potential benefits as well as the risks (overdiagnosis and overtherapy) shall be presented in natural numbers and also graphically. Similarly, the significance of positive and negative test results shall be presented.

Recommendation 4.1

If there is a reason for providing information about early detection of prostate cancer, men shall be given open and unbiased advice about the advantages and disadvantages, in particular with regard to the significance of positive and negative test results, overdiagnosis, and any further measures that may be required.

Recommendation 4.2

Men who wish to have a screening examination after education shall be offered the determination of the PSA value as an examination method.

In addition, a digital-rectal examination should be recommended.

Recommendation 4.2

Men who wish to have a screening examination after informed consent shall be offered testing to determinate their PSA value as an examination method.

In addition, a digital-rectal examination can be performed.

Statement 4.3

For the early detection of prostate cancer, imaging techniques are not suitable as a primary examination.

Statement 4.3 (remained unchanged)

For the early detection of prostate cancer, imaging techniques are not suitable as a primary examination.

Recommendation 4.4

An elevated PSA value shall be monitored taking into account influencing factors.

Recommendation 4.4 (remained unchanged)

An elevated PSA value shall be monitored taking into account influencing factors.

Recommendation 4.5

For men who wish to continue PSA screening, the follow-up interval should be based on the patient's current PSA level and age, unless there is an indication for biopsy.

Age group 45 years and older and a life expectancy > 10 years.

• PSA < 1 ng/ml: interval every 4 years
• PSA 1-2 ng/ml: interval every 2 years
• PSA > 2 ng/ml: interval every year

For men over 70 years of age and a PSA < 1ng/ml, further PSA-based screening is not recommended.

Recommendation 4.5 (remained unchanged)

For men who wish to continue PSA screening, the follow-up interval should be based on the patient's current PSA level and age, unless there is an indication for biopsy.

Age group 45 years and older and a life expectancy > 10 years.

• PSA < 1 ng/ml: interval every 4 years
• PSA 1-2 ng/ml: interval every 2 years
• PSA > 2 ng/ml: interval every year

For men over 70 years of age and a PSA < 1ng/ml, further PSA-based screening is not recommended.

Recommendation 4.6

In the context of screening, prostate biopsy shall be recommended if at least one of the following criteria is met:

• Screening PSA level of ≥ 4 ng/ml at the initial screening consultation, taking into account influencing factors;
• Result suspicious for carcinoma on digital-rectal examination;
• Abnormal PSA increase (without change in the method used for determination).

Recommendation 4.6 (remained unchanged)

In the context of screening, prostate biopsy shall be recommended if at least one of the following criteria is met:

Chapter 5 Diagnosis and Staging

Recommendation 5.13

MRI of the prostate shall be performed multiparametrically according to current quality standards.

(For indication see 5.15 to 5.18.)

Recommendation 5.13 (editorial changes)

MRI of the prostate shall be performed multiparametrically (mpMRI) according to current quality standards.

(For indication see 5.15 to 5.18.)

Recommendation 5.14

a. The carcinoma-suspected foci described on prostate MRI shall be targeted for biopsy.

b. In addition to the MRI-targeted biopsy, a systematic biopsy should be performed simultaneously

Recommendation 5.14

a. The foci which are suspicious for carcinoma as described on mpMRI shall be biopsied in a targeted manner.

b. In addition to the mpMRI-targeted biopsy, a systematic biopsy should be performed as part of the initial biopsy.

Statement 5.15

The majority of study results on MRI-guided vs. systematic biopsy vs. a combination of both procedures in previously biopsy-naïve men indicate that MRI-guided biopsy detects significant cancers slightly more frequently (in the range of 10%) than systematic biopsy alone. However, significant cancers are missed in MRI and targeted biopsy, just as systematic biopsy fails to detect a relevant proportion (in the range of 20%). The combination of an MRI-guided targeted approach plus systematic biopsy achieves better detection rates than either method alone.

Statement 5.15 (editiorial changes)

The majority of study results on mpMRI-guided vs. systematic biopsy vs. a combination of both procedures in previously biopsy-naïve men indicate that mpMRI-guided biopsy detects significant cancers slightly more frequently (in the range of 10%) than systematic biopsy alone. However, significant cancers are missed in mpMRI and targeted biopsy, just as systematic biopsy fails to detect a relevant proportion (in the range of 20%). The combination of an mpMRI-guided targeted approach plus systematic biopsy achieves better detection rates than either method alone.

Recommendation 5.16

a. MRI according to current quality standards can be used as part of primary diagnosis. However, it is not part of the diagnostic routine.

b. An inconspicuous result on mpMRI (PI-RADS <3) carries a residual risk of significant tumors, such that a systematic biopsy should be offered in addition to PSA-based monitoring.

Recommendation 5.16

a. mpMRI according to current quality standards should be used as part of primary diagnosis.

b. A normal result on mpMRI (PI-RADS <3) carries a residual risk of significant tumors, such that a systematic biopsy should be offered in addition to PSA-based monitoring.

Recommendation 5.17

a. After negative systematic biopsy without prior MRI, if carcinoma is still suspected, imaging by MRI should be performed according to the applicable quality standards.

b. After negative rebiopsy (MRI-guided plus systemic biopsy), no further invasive intervention should be performed if clinical parameters (DRE and PSA) remain unchanged.

c. After negative rebiopsy (MRI-guided plus systemic biopsy), no further imaging procedure should be performed if clinical parameters (DRE and PSA) remain unchanged.

Recommendation 5.17

a. After negative systematic biopsy without prior mpMRI, if carcinoma is still suspected, imaging by mpMRI shall be performed according to the applicable quality standards.

b. After negative rebiopsy, no further invasive intervention shall be performed if clinical parameters (DRE and PSA) remain unchanged.

Recommendation 5.18

a. Patients considering Active Surveillance as a treatment option shall be given an MRI that meets current quality standards prior to this being indicated.

b. If suspicious areas (PI-RADS) are seen on MRI, they shall be targeted for biopsy.

Recommendation 5.18

a. Patients considering Active Surveillance shall be given an mpMRI that meets current quality standards prior to this being indicated.

b. If suspicious areas (PI-RADS 3-5) are seen on mpMRI, they shall be targeted for biopsy.

Recommendation 5.25

Recommendation/Statement 5.25

a.PSMA-PET has a higher accuracy (precision) for detecting prostate cancer metastases than the combination of computed tomography and bone scintigraphy.

b. PSMA-PET/CT can be used in high-risk prostate cancer (Gleason score 8-10 or T category cT3/cT4 or PSA≥20ng/ml) for diagnosis of metastasis.

Chapter 6.3 Local treatments for localized prostate carcinoma

Statement 6.25

Interstitial LDR monotherapy is a primary therapeutic option for the treatment of localized prostate cancer with a low-risk profile.

Statement 6.25 (remained unchanged)

Interstitial LDR monotherapy is a primary therapeutic option for the treatment of localized prostate cancer with a low-risk profile.

There can still be no recommendation made regarding LDR brachytherapy in patients with localized prostate carcinoma of the intermediate-risk profile due to the heterogeneous state of the literature (see background text 6.26).

Statement removed

Recommendation 6.26

Patients with high-risk prostate cancer shall not receive LDR monotherapy.

Recommendation 6.26 (remained unchanged)

Patients with high-risk prostate cancer shall not receive LDR monotherapy.

Recommendation 6.27

The combination of LDR brachytherapy with percutaneous radiotherapy and/or hormone ablative therapy for patients with high-risk prostate cancer shall be reserved for controlled trials.

Recommendation 6.27

a. For intermediate- or high-risk localized prostate cancer, primary combined percutaneous radiation plus LDR/HDR brachytherapy boost can be performed in conjunction with short-term or long-term androgen deprivation therapy (ADT).

b. Patients shall be educated about the significant increase in late toxicity (≥ grade 3) associated with this form of therapy.

c. Androgen deprivation therapy (ADT) shall be used when brachytherapy is used, analogously to the recommendations for percutaneous radiotherapy.

Recommendation 6.28

HDR brachytherapy, combined with percutaneous radiotherapy, is a primary treatment option for localized prostate cancer.

Recommendation 6.28 (remained unchanged)

HDR brachytherapy, combined with percutaneous radiotherapy, is a primary treatment option for localized prostate cancer.

Statement 6.29

a. HDR brachytherapy, combined with percutaneous radiotherapy, is a primary treatment option for patients with intermediate and high-risk profile tumors.

b. The value of additional hormone-ablation therapy has not been clarified.

Statement 6.29 (remained unchanged)

a. HDR brachytherapy, combined with percutaneous radiotherapy, is a primary treatment option for patients with intermediate and high-risk profile tumors.

b. The value of additional hormone-ablation therapy has not been clarified.

Recommendation 6.30

HDR monotherapy in patients with low-risk profile tumors shall be used exclusively in controlled trials.

Recommendation 6.30 (remained unchanged)

HDR monotherapy in patients with low-risk profile tumors shall be used exclusively in controlled trials.

Statement 6.36

In focal therapy for localized prostate cancer, only part of the prostate is treated.

Statement 6.37

The goal of focal therapy for localized prostate cancer is the eradication of all significant tumors.

Recommendation 6.38

Patients with low-risk unilateral localized prostate cancer can be offered focal therapy if they decline both standard therapies and Active Surveillance (AS) and meet the following requirements:

- Gleason Score 6

- PSA < 10 ng/ml

- inconspicuous palpation

- maximum 50 % positive biopsies only on one side in the systematic biopsy

- diagnosis by mpMRI, fusion biopsy and systematic biopsy.

Recommendation 6.39

a. Patients considering focal therapy shall receive mpMRI, mpMRI fusion biopsy, and systematic biopsy.

b. Alternatively, if MRI fusion biopsy is not feasible, a template-based biopsy can be performed.

Recommendation 6.40

a. Patient education on focal therapy shall include the fact that there is no evidence that the therapy is equivalent to standard therapies.

b. In the event that salvage therapy is required, patient education about focal therapy shall include, in addition to what is described in recommendation a., reference to potentially worse functional and oncological outcomes of salvage therapy.

Recommendation 6.41

When following the Active Surveillance strategy, a targeted and a systematic biopsy shall be performed 6 to 12 months after focal therapy (treated area targeted and the remaining gland additionally biopsied systematically).

Recommendation 6.36
Hyperthermia alone should not be used in the primary therapy of localized prostate cancer.

Recommendation 6.37
Whole-gland HIFU therapy is an experimental procedure in localized prostate cancer and should only be used in prospective studies.

Recommendation 6.38
Focal therapies as treatment of a part of the prostate in localized prostate cancer have a highly experimental character and should only be used in the context of prospective studies.

Recommendation 6.39
Cryotherapy is not an adequate treatment alternative in the primary therapy of localized prostate carcinoma. There are no study data to justify the use of this procedure in the primary therapy of localized PCa.

Statement 6.42

There are no comparative data available comparing the different technologies for focal therapy that would allow an assessment of efficacy, side effects, and safety parameters.

Statement 6.43

Focal vascular-targeted photodynamic therapy (VTP) using padeliporfin is the only focal technology for which results are available from a prospective randomized-controlled trial comparing focal therapy for low-risk prostate cancer with active surveillance.

Statement 6.44

There are insufficient data to assess the oncological efficacy and safety of focal high-intensity focused ultrasound ablation (HIFU).

Statement 6.45

There are insufficient data to assess the oncological efficacy and safety of focal cryotherapy.

Statement 6.46

There are insufficient data to assess the oncological efficacy and safety of focal irreversible electroporation (IRE), particularly in terms of long-term outcomes.

Statement 6.47

There are insufficient data to assess the oncological efficacy and safety of focal laser ablation, focal brachytherapy, focal radiofrequency ablation (RFA), focal stereotactic radiation therapy (SBRT), focal microwave therapy, and focal transurethral ultrasound ablation.

Chapter 6.4 Local treatment of locally-advanced prostate carcinoma

Chapter 6.4 Local treatment of locally- advanced prostate carcinoma

Statement 6.49

In patients with locally advanced prostate cancer of clinical category cT3, HDR brachytherapy combined with percutaneous radiation is a therapeutic option. For tumors of clinical category cT4, HDR brachytherapy is not indicated.

The same criteria apply for additional hormone ablative therapy as for combined hormone radiotherapy alone.

Recommendation 6.57

In patients with locally-advanced prostate carcinoma of clinical category cT3, HDR brachytherapy combined with percutaneous radiation is a treatment option. In tumors of clinical category cT4, HDR brachytherapy is not indicated.

The same criteria apply for additional hormone-ablation therapy as for combined hormone radiotherapy alone.

Recommendation 6.60

Patients with locally-advanced prostate cancer shall not receive focal therapy – with any technology.

Statement 6.55

Adjuvant percutaneous radiotherapy is the term used for radiotherapy following radical prostatectomy after the defined PSA zero range has been reached.

(For treatment in the case of PSA levels persisting postoperatively, see chapter 7.2. For definition of PSA progression, see chapter 7.1).

Statement 6.61 (remained unchanged)

Adjuvant percutaneous radiotherapy is the term used for radiotherapy following radical prostatectomy after the defined PSA zero range has been reached.

(For treatment in the case of PSA levels persisting postoperatively, see chapter 7.2. For definition of PSA progression, see chapter 7.1).

Recommendation 6.56

a. Patients with pT3pN0 tumors with positive resection margins should be offered adjuvant radiotherapy as an option with informed benefit and risk.

b. Patients with pT3 tumors and negative resection margins but other risk factors such as seminal vesicle infiltration should be offered adjuvant radiotherapy as an option with explanation of benefits and risks, with a lower expected effect than with positive resection margins.

c. Patients with pT2 tumors with positive resection margins may be offered adjuvant radiotherapy with explanation of the benefits and risks.

d. For each of the three groups (a-c), the alternative option of percutaneous radiotherapy for PSA rise from the defined zero range should be mentioned during the adjuvant radiotherapy education (see Chapter 7.2 for treatment of PSA recurrence).

Recommendation 6.62

The indication for adjuvant radiotherapy is limited to the following high-risk groups:

a. Patients with high-risk locally-advanced prostate carcinoma (pN0) and the following factors should be offered adjuvant radiotherapy as an option with informed benefit and risk: pT3/pT4+R1 (positive cut margin) + Gleason score 8-10 (ISUP 4-5).

b. Patients with locally advanced prostate cancer (pN0) at increased risk and the following factors can be offered adjuvant radiotherapy as an option with informed benefit and risk: pT3/pT4+R0 (negative cut margin) + Gleason score 8-10 (ISUP 4-5).

c. Patients with localized prostate carcinoma (pN0) and the following factors can be offered adjuvant radiotherapy as an option with explanation of benefits and risks: R1 (multifocal positive incisional margin) + Gleason score 8-10 + pT2.

d. For each of the three groups (a-c), the alternative option of percutaneous radiotherapy for a rise in PSA from the defined zero range shall be mentioned as part of patient education on adjuvant radiotherapy (see Section 7.2 for treatment of PSA recurrence).

Chapter 7.2 Therapy of PSA recurrence

Statement 7.8

In patients with PSA recurrence and favorable prognostic criteria (see background information), wait-and-see is an option.

Statement 7.8

In patients with PSA recurrence and favorable prognostic criteria (PSA doubling time of > 12 months, Gleason score < 8 (ISUP <4)), wait-and-see is an option.

Recommendation 7.9

Percutaneous salvage radiotherapy (SRT) (min. 66 Gy) should be offered as a treatment option following radical prostatectomy for a PSA rise from the zero range in the pN0/NX category.

Recommendation 7.9

Percutaneous salvage radiotherapy (SRT) (min. 66 Gy) shall be offered as a treatment option following radical prostatectomy for a PSA rise from the zero range in the pN0/NX category.

Recommendation 7.10

Patients at high risk of progression (PSA before SRT > 0.7 ng/ml) shall be offered androgen deprivation therapy (ADT) or bicalutamide in addition to percutaneous salvage radiotherapy (SRT).

Recommendation 7.11

Percutaneous salvage radiotherapy (SRT) (min. 66 Gy) shall be offered in combination with androgen deprivation therapy (ADT) as a treatment option after radical prostatectomy for a PSA rise from the zero range and unfavorable prognostic criteria (PSA doubling time < 12 months, Gleason 8-10 (ISUP 4-5)) in the pN0/NX category.

Recommendation 7.12

If androgen deprivation therapy (ADT) is added to percutaneous radiotherapy (SRT), the duration of ADT can be based on the risk of progression (high risk of progression: 24 months; or increased risk of progression: 6 months).

Recommendation 7.10

a. Salvage radiotherapy shall be started as early as possible (PSA before SRT).

b. With initial stage pN0 and early start to radiotherapy, lymphatic drainage pathways should not be irradiated.

Recommendation 7.13 (remained unchanged)

a. Salvage radiotherapy shall be started as early as possible (PSA before SRT).

b. With initial stage pN0 and early start to radiotherapy, lymphatic drainage pathways should not be irradiated.

Recommendation 7.11

Treatment of persistent PSA level (above the defined zero range) after radical prostatectomy can be performed according to the above principles of treatment of PSA recurrence.

Recommendation 7.14

Treatment of persistent PSA levels (above the defined zero range) following radical prostatectomy should follow the above principles of treatment for PSA recurrence.

Chapter 7.3 Treatment of hormone-sensitive metastatic prostate carcinoma (mHSPC)

Statement 7.17

The options of combined hormone therapy with docetaxel or with abiraterone (plus prednisone/prednisolone) have fundamentally changed the first-line treatment of metastatic (M1), hormone-sensitive prostate cancer at initial diagnosis.

Statement removed

Recommendation 7.20

Patients with metastatic hormone-sensitive prostate cancer (mHSPC) shall be classified as high and low-volume as well as high and low-risk.

Recommendation 7.18

Part of the information about sole androgen deprivation or combination therapy shall be the following points in particular:

-the palliative nature of the therapy;

-impact on quality of life;

-the adverse effects.

Recommendation 7.21 (editorial changes)

Part of the patient education about androgen deprivation alone or combination therapy shall include the following points in particular:

•the palliative nature of the therapy;

•impact on quality of life;

•the adverse effects.

Recommendation 7.19

Patients in good general health (ECOG 0-1) with metastatic (M1), hormone-sensitive prostate cancer should be recommended chemotherapy with docetaxel or supplemental antihormonal therapy with abiraterone (plus prednisone/prednisolone) in addition to androgen deprivation.

Recommendation 7.22

a. Patients in good general health (ECOG 0-1) with metastatic (M1), hormone-sensitive, prostate cancer (mHSPC) shall be offered hormone therapy with apalutamide in addition to androgen deprivation.

b. Patients in good general health (ECOG 0-1) with metastatic (M1), hormone-sensitive, prostate carcinoma (mHSPC) shall be offered hormone therapy with enzalutamide in addition to androgen deprivation.

c. Patients in good general condition (ECOG 0-1) with newly-diagnosed (de novo), metastatic (M1), hormone-sensitive, high-risk prostate cancer (mHSPC) shall be offered hormone therapy with abiraterone (plus prednisone/prednisolone) in addition to androgen deprivation.

d. Patients in good general condition (ECOG 0-1) with metastatic (M1), hormone-sensitive, high-volume prostate carcinoma (mHSPC) shall be offered chemotherapy with docetaxel in addition to androgen deprivation, with education about the higher toxicity compared with new hormonal agents.

e. Patients in good general health (ECOG 0-1) with metastatic (M1), hormone-sensitive, low-volume prostate cancer (mHSPC) can be offered chemotherapy with docetaxel in addition to androgen deprivation.

Statement/Recommendation 7.20

It is currently unclear which patient groups will benefit more from which combination therapy

The therapy decision should be made depending on patient preferences, side effects and concomitant diseases.

Recommendation 7.23

The therapeutic decision should be made depending on patient preferences, side effects and concomitant diseases.

Recommendation 7.21

a. If the patient chooses combined treatment of chemotherapy and androgen deprivation, docetaxel should be started within 4 months of the start of androgen deprivation. 6 cycles every three weeks at a dosage of 75mg/m² should be given.

b. If the patient chooses combined treatment of androgen deprivation and abiraterone, abiraterone administration should begin within 3 months of the start of androgen deprivation. Therapy should be given at a dosage of 1000 mg/day in combination with prednisone or prednisolone (5 mg/day).

c. Reasons for discontinuation should be: patient request, progression, or intolerable side effects.

Recommendation 7.24

a. If combined treatment of androgen deprivation and apalutamide is decided upon, apalutamide administration shall begin within 3 months of initiation of androgen deprivation. Therapy should be given at a dose of 240 mg/day.

b. If combined treatment of androgen deprivation and enzalutamide is decided upon, enzalutamide administration shall begin within 3 months of the start of androgen deprivation. Therapy should be given at a dose of 160 mg/day.

c. If combined treatment of androgen deprivation and abiraterone is chosen, abiraterone administration shall begin within 3 months of initiation of androgen deprivation. Therapy shall be given at a dose of 1000 mg/day in combination with prednisone or prednisolone (5 mg/day).

d. If combined treatment of chemotherapy and androgen deprivation is decided, docetaxel administration shall begin within 4 months of the start of androgen deprivation. 6 cycles every three weeks at a dose of 75mg/m² shall be given.

e. Reasons for discontinuation of therapy shall include: patient request, progression, or intolerable side effects.

Recommendation 7.22

a. Patients who are not eligible for combination treatment shall be recommended for androgen deprivation.

b. Androgen deprivation can be performed with medication or surgery.

c. Drug androgen deprivation can be given as monotherapy or as maximal androgen blockade.

d. Androgen deprivation should be performed continuously if the PSA level does not fall below 4 ng/mL after 7 months at the latest.

e. If the PSA level falls below 4 ng/mL, intermittent hormone therapy may be offered as an alternative after detailed explanation.

Recommendation 7.25

a. Patients who are not eligible for combination treatment shall be recommended for androgen deprivation.

b. Androgen deprivation can be performed by medication or surgery.

c. Androgen deprivation should be performed continuously if the PSA level does not fall below 4 ng/mL after at least 7 months.

d. If the PSA level drops below 4 ng/mL, intermittent hormone therapy can be offered as an alternative after detailed patient education is provided.

7.4. Treatment of androgen-independent or castration-resistant prostate cancer (CRPC)

Recommendation 7.23

Patients with castration-resistant prostate cancer shall be provided with information about the following:

• A cure cannot be achieved.
• Various options are available for further treatment.

Recommendation 7.26 (remained unchanged)

Patients with castration-resistant prostate cancer shall be provided with information about the following:

• A cure cannot be achieved.
• Various options are available for further treatment.

Recommendation 7.24

In patients with symptomatic progressive disease undergoing castration with medication, therapeutic options and the therapeutic approach should be discussed and determined on an interdisciplinary basis.

Recommendation 7.27 (remained unchanged)

Recommendation 7.25

The following factors shall be considered when making a treatment decision:
• symptoms
• side effects of treatment options
• patient preference
• comorbidities, life expectancy, and quality of life
• progression over time
• localization of metastases and general tumor burden.

Recommendation 7.28 (remained unchanged)

Statement 7.26

Suitability for treatment with chemotherapy is not a clearly defined variable. Therefore, there is a lack of threshold values above which suitability for treatment can be determined or otherwise.

Statement 7.29 (remained unchanged)

Suitability for treatment with chemotherapy is not a clearly defined variable. Therefore, there is a lack of threshold values above which suitability for treatment can be determined or otherwise.

Statement 7.27

A geriatric assessment is useful for decision making before initiating tumor-specific therapy in multimorbid patients older than 70 years.

Statement 7.30 (remained unchanged)

A geriatric assessment is useful for decision making before initiating tumor-specific therapy in multimorbid patients older than 70 years.

Recommendation 7.28

Serum testosterone levels shall be monitored in patients with progressive disease undergoing surgical or drug castration therapy.

Recommendation 7.31 (remained unchanged)

Serum testosterone levels shall be monitored in patients with progressive disease undergoing surgical or drug castration therapy.

Recommendation 7.29

Patients with castration-resistant, asymptomatic, or mildly symptomatic progressive disease without imaging evidence of metastases shall be offered a wait-and-see approach while maintaining androgen deprivation.

Recommendation removed

Recommendation 7.32

Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and a high risk of metastasis (PSA doubling time of <10 months) shall be offered apalutamide, darolutamide, or enzalutamide (alphabetical order) in addition to androgen deprivation therapy (ADT).

Recommendation 7.33

The indication for intensified treatment according to 7.32 should take into account presumed life expectancy (based on age, among other factors) as well as potential adverse effects and quality of life.

Recommendation 7.30

Patients with metastatic, castration-resistant, asymptomatic or mildly-symptomatic and progressive disease who are taking an androgen deprivation treatment can be offered a change of treatment provided the benefits and side effects are explained to them. The specific conditions and side effects of the therapies should be taken into account.

Recommendation 7.34 (remained unchanged)

Recommendation 7.31

When a patient with metastatic, castration-resistant, asymptomatic, or low-symptomatic and progressive disease has decided against a wait-and-see approach, opting to switch treatment, one of the following options shall be offered:

(alphabetical order)

· abiraterone (in combination with prednisone/prednisolone)

· docetaxel

· enzalutamide

For differential therapy, see Recommendations 7.36 and 7.37.

Recommendation 7.35 (remained unchanged)

(alphabetical order)

· abiraterone (in combination with prednisone/prednisolone)

· docetaxel

· enzalutamide

For differential therapy, see Recommendations 7.36 and 7.37.

Recommendation 7.32

Patients with metastatic, castration-resistant, asymptomatic, or low-symptomatic and progressive disease should be offered

(in alphabetical order)

- Abiraterone (in combination with prednisone / prednisolone) or

- enzalutamide

as first-line therapy.

Recommendation 7.36 (editorial changes)

Patients with metastatic, castration-resistant, asymptomatic, or mildly-symptomatic and progressive disease should be offered (in alphapetical order):

· abiraterone (in combination with prednisone/prednisolone); or

· enzalutamide

Recommendation 7.33

Patients with metastatic, castration-resistant, asymptomatic, or mildly symptomatic and progressive disease may be offered docetaxel as first-line therapy.

Recommendation 7.37 (editorial changes)

Patients with metastatic, castration-resistant, asymptomatic, or mildly-symptomatic and progressive disease can be offered docetaxel.

Recommendation 7.34

Patients with metastatic, castration-resistant, symptomatic, progressive
disease and good general condition should be treated with a systemic
systemic therapy as first-line therapy, if necessary in combination with symptomatic with symptom-based and supportive therapy, as first-line therapy.
For differential therapy, see recommendations 7.35, 7.36, 7.37.

Recommendation 7.38 (editorial changes)

Patients with metastatic, castration-resistant, symptomatic progressive disease who are in a good general condition shall be offered systemic therapy, if necessary in combination with symptom-related and supportive therapy. For differential therapy, see Recommendations 7.39, 7.40, 7.41.

Recommendation 7.35

Patients with metastatic, castration-resistant, symptomatic, and progressive disease may be offered docetaxel as first-line therapy in two- or three-week dosing regimens.

Recommendation 7.39 (editorial changes)

Patients with metastatic, castration-resistant, symptomatic, and progressive disease can be offered docetaxel in two or three-week dosing regimens.

Recommendation 7.36

Patients with metastatic, castration-resistant, symptomatic, and progressive disease can be offered
(in alphabetical order)

• abiraterone (in combination with prednisone/prednisolone) or

• enzalutamide

as first-line therapy.

Patients should be informed that only patients with low symptomatic disease were treated in the pivotal study.

Recommendation 7.40 (editorial changes)

Patients with metastatic, castration-resistant, symptomatic, and progressive disease can be offered:

(in alphabetical order)

• abiraterone (in combination with prednisone/prednisolone); or

• enzalutamide

Patients shall be informed that only patients with low symptomatic disease were treated in the pivotal study.

Recommendation 7.37

Patients with castration-resistant, symptomatic, progressive disease with osseous metastases without evidence of extra-osseous distant metastases may be offered radium-223 as first-line therapy.

Recommendation removed

Recommendation 7.38

Patients with castration-resistant, symptomatic, progressive disease and reduced general condition (ECOG ≥ 2, Karnofsky index < 70) shall be offered symptom-based therapy.

Recommendation 7.41 (remained unchanged)

Patients with castration-resistant, symptomatic, progressive disease and reduced general condition (ECOG ≥ 2, Karnofsky index < 70) shall be offered symptom-based therapy.

Recommendation 7.39

Patients with castration-resistant, progressive disease and reduced general condition (ECOG ≥ 2, Karnofsky index < 70) may additionally be offered one of the following treatment options as first-line therapy:

(in alphabetical order)

· abiraterone (in combination with prednisone / prednisolone);

· chemotherapy, if the reduced general condition is primarily due to the metastatic prostate cancer;

· enzalutamide;

• radium-223 for osseous metastasis

· steroids (dexamethasone, prednisolone, prednisone).

Recommendation 7.42

Patients with castration-resistant, progressive disease and reduced general condition (ECOG ≥ 2, Karnofsky index <70) can additionally be offered one of the following treatment options:

(in alphabetical order)

· abiraterone (in combination with prednisone / prednisolone);

· chemotherapy, if the reduced general condition is primarily due to the metastatic prostate cancer;

· enzalutamide;

· steroids (dexamethasone, prednisolone, prednisone).

Recommendation 7.43

Patients with progression under a new hormonal agent (NHA) should be offered a change in therapeutic strategy.

Recommendation 7.44

Patients with progression after pre-therapy that included a new hormonal agent shall be offered testing for BRCA 1/2 mutations.

Recommendation 7.45

If a BRCA1/2 mutation is detected, therapy with olaparib shall be offered.

Recommendation 7.40

Patients with castration-resistant, progressive disease and good general health after chemotherapy with docetaxel shall be offered one of the following treatment options, in combination with symptom-based and supportive therapy if needed:

(in alphabetical order)

· Abiraterone (in combination with prednisone/prednisolone).

· Cabazitaxel

· Enzalutamide

Radionuclide therapy with radium-223 for osseous metastasis.

For differential therapy, see Recommendations 7.47 - 7.49.

Recommendation 7.46

(in alphabetical order)

· Abiraterone (in combination with prednisone/prednisolone).

· Cabazitaxel

· Enzalutamide

For differential therapy, see Recommendations 7.47 - 7.49.

Recommendation 7.41

Patients with castration-resistant, progressive disease and good general condition after chemotherapy with docetaxel can be offered:

(alphabetical order)

• Abiraterone (in combination with prednisone/prednisolone) or

• Enzalutamide

A prolongation of survival was shown in the respective pivotal trial.

Recommendation 7.47 (remained unchanged)

Patients with castration-resistant, progressive disease and good general condition after chemotherapy with docetaxel can be offered:

(alphabetical order)

• Abiraterone (in combination with prednisone/prednisolone) or

• Enzalutamide

A prolongation of survival was shown in the respective pivotal trial.

Recommendation 7.42

Cabazitaxel can be offered to patients with castration-resistant, progressive disease and good general condition after chemotherapy with docetaxel. A prolongation of survival was shown in the pivotal trial.

Recommendation 7.48 (remained unchanged)

Recommendation 7.43

Patients with castration-resistant, progressive disease and good general condition after chemotherapy with docetaxel can be offered radium-223 for osseous metastases. Prolongation of survival was shown in the pivotal study.

Recommendation 7.49

a. Radium-223 can be offered to patients who have castration-resistant, progressive prostate cancer with symptomatic osseous metastases (without known visceral metastases) and good general health, and who have received at least two prior systemic therapy options in this indication, or for whom no other available systemic mCRPC therapy is suitable.

b. Radium-223 shall not be used in combination with abiraterone and prednisone/prednisolone.

Recommendation 7.44

Patients with castration-resistant, progressive disease after chemotherapy with docetaxel and reduced general condition (ECOG ≥ 2, Karnofsky < 70) may be offered one of the following treatment options in addition to symptom-based therapy:

(in alphabetical order)

· Abiraterone (in combination with prednisone/prednisolone).

· Chemotherapy if the reduced general condition is primarily due to metastatic prostate cancer

· Enzalutamide

• Radionuclide therapy with radium-223 for osseous metastasis

· Steroids (dexamethasone, prednisolone, prednisone).

Recommendation 7.50

Patients with castration-resistant, progressive disease after chemotherapy with docetaxel and reduced general condition (ECOG ≥ 2, Karnofsky <70) can be offered one of the following treatment options, in addition to a symptom-based therapy:

(in alphabetical order)

· Abiraterone (in combination with prednisone/prednisolone).

· Chemotherapy if the reduced general condition is primarily due to metastatic prostate cancer

· Enzalutamide

· Steroids (dexamethasone, prednisolone, prednisone).

Recommendation 7.45

For patients with castration-resistant, progressive disease in good general health, a trial of therapy with lutetium-177-PSMA can be offered based on the recommendation of an interdisciplinary tumor conference after other recommended therapeutic options (see Recommendation 7.46) are exhausted.

Recommendation 7.51 (remained unchanged)

Recommendation 7.46

Patients with castration-resistant, progressive disease and good general condition after first-line androgen receptor-targeted therapy can be offered sequential therapy using one of the other effective drugs (see Recommendation 7.40).

Recommendation 7.52 (editorial changes)

Patients with castration-resistant, progressive disease and good general condition after androgen receptor-targeted therapy can be offered sequential therapy using one of the other effective drugs (see Recommendation 7.46).

Chapter 7.5 Local treatment for metastatic prostate cancer

Statement 7.53

Oligometastatic prostate cancer is defined as a tumor with a maximum of 4 bone metastases detectable on conventional imaging (skeletal scintigraphy and CT or MRI) without extraosseous visceral metastases.

Recommendation 7.54

a. Patients with newly diagnosed oligometastatic prostate cancer should receive percutaneous radiotherapy of the prostate in addition to systemic therapy.

b. External beam radiotherapy (EBRT) should be administered in a hypofractionated manner, and the radiation dose should not exceed an equivalent dose of 72 Gy in 2 Gy standard fractionation.

Recommendation 7.55

Percutaneous radiotherapy of the prostate can be combined with extended systemic therapy (androgen deprivation (ADT) simultaneous, docetaxel sequential) in oligometastatic prostate cancer.

Recommendation/Statement 7.56

a. Radical prostatectomy is not adequately supported by evidence as a treatment option for oligometastatic prostate cancer.

b. Radical prostatectomy can be offered for oligometastatic prostate cancer after discussion in an interdisciplinary tumor conference as part of multimodality therapy.

Recommendation/Statement 7.57

a. Metastasis-directed local ablative therapy for oligometastatic prostate cancer is not adequately supported by evidence, particularly with regard to oncological outcomes.

b. Metastasis-directed local ablative therapy for oligometastatic prostate cancer can be used to delay androgen deprivation and/or tumor progression.

c. External beam radiation therapy (EBRT) as ablative treatment should be hypofractionated, preferably as stereotactic radiation (SBRT).

Chapter 7.5 Therapy of bone metastases

Chapter 7.6 Therapy of bone metastases

Evidence-based Recommendation 7.49

Radionuclides can be used for pain management in multiple bone metastases at castration-resistant stage. Radium-223 therapy leads to prolonged survival in patients in good general condition (ECOG ≤ 2) without evidence of visceral metastases.

Recommendation 7.60

Radionuclides can be used for pain treatment in multiple bone metastases in the castration-resistant stage. Please refer to Recommendation 7.49 for the indication of radium-223.

13.3 Comparative overview of the side effect profile of prostate carcinoma treatments

Table 25: Comparative overview of the side effect profile of prostate carcinoma treatments

	Radical prostatectomy including nerve-sparing operations	EBRT	LDR	HDR
Erectile dysfunction
Dutch Urological Association 2007 (guideline) [190]	70% markedly reduced by nerve sparing operation (14%-56,6%)	50-70%	10-70%	n/a
EAU 2007 (guideline) [96]	29-100% (56% nerve sparing, 75% standard) Late effect: 75% both	45% Late effect (2y): 48%	34% Late effect (1y): 34%	40.86% Late effect (2y): 40%
Wilt 2008 (syst. review) [325]	< 5-86%	77%	n/a	n/a
U.S. Preventive Services Task Force, 2002 (syst. review) [326]	20-70%	20-45%	45-57%	n/a
Mambourg 2006 (HTA) [327]	76-80%	45-63,5%	36% (?)	n/a
Vargas 2005 [332], Grills 2004 [333] (cohort studies)	--	--	--	45-61,6%
Urinary disturbances (urinary incontinence/emptying disturbances)
Dutch Urological Association 2007 (guideline) [190]	5-10% (persistent incontinence)	30-40% (acute form of incontinence) 1-7,2% late urinary symptoms	5-10% (acute retention)	n/a
EAU 2007 (guideline) [96]	0-50% (incl. fistula 0,3-15,4%)	15,9% (5,3% incontinence)	1,5-22% (acute retention) Incontinence 0-19% Chronical urinary morbidity: = 20%	--
Wilt 2008 (syst. review) [325]	5-62 %	2-23,9 %	2-32 %	n/a
U.S. Preventive Services Task Force 2002 (syst. review) [326]	15-50%	2-16%	6-57%	n/a
Mambourg 2006 (HTA) [327]	10-20%	n/a	n/a	n/a
Vargas 2005 [332] (only reported for toxicity grades 3-4), Grills 2004 [333] (cohort studies)	--	--	--	13,7-32%
Interstinal problems (without hemorrhage)
Dutch Urological Association 2007 (guideline) [190]	none	30% (persistent events: 10%)	3-21 % (grade II/III proctitis)	n/a
EAU 2007 (guideline) [96]	none	12,4 % (only persistent events)	--	--
Wilt 2008 (syst. review) [325]	15%	31,8&	8-13	5
U.S. Preventive Services Task Force 2002 (syst. review) [326]	0%	6-25%	18%	n/a
Mambourg 2006 (HTA) [327]	20,9-23,9%	26,7-435	n/a	n/a
Vargas 2005 [332] (only reported for toxicity grades 3-4), Grills 2004 [333] (cohort studies)	--	--	--	3,9-6%
Other adverse effects
Rectal hemorrhage
Dutch Urological Association 2007 (guideline) [190]	--	< 30%, 8% required treatment	n/a	n/a
Wilt 2008 (syst. review) [325]	n/a	n/a	n/a	n/a
U.S. Preventive Services Task Force 2002 (syst. review) [326]	n/a	n/a	19%	n/a
Mambourg 2006 (HTA) [327]	0%	8-25%	n/a	n/a
Grills 2004 (cohort studies) [333]	--	--	--	2%
Rectal injury
EAU 2007 (guideline) [96]	0-5,4%	--	--	--
Radiation-induced carcinoma
Dutch Urological Association 2007 (guideline) [190]	--	RR 1-1,7	--	--
EAU 2007 (guideline) [96]	--	RR 1,7-2,34 (Baxter, Liauw, s.u.)	--	--

References

[190] Dutch Urological Association, Prostate Cancer. Nation-wide guideline. Version 1.0Dutch Urological Association, 2007.

[96] Heidenreich, A., Aus, G., Abbou, C.C., Bolla, M., Joniau, S., Matveev, V., et.al. EAU guidelines on prostate cancerEAU, 2007.

[325] Wilt, T.J., MacDonald, R., Rutks, I., Shamliyan, T.A., Taylor, B.C., Kane, R.L., Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer, Ann. Intern. Med, 2008. 148(6): p. 435-448., http://www.ncbi.nlm.nih.gov/pubmed/18252677

[326] U.S.Preventive Services Task Force, Screening for prostate cancer: recommendation and rationale, Annals of Internal Medicine, 2002. 137(11): p. 915-916.

[327] Mambourg, F., van den Bruel, A., Devries, S., Leys, M., Vinck, I., Lona, M., et.al. HTA of prostate cancer screeningBelgian Health Care Knowledge Centre (KCE), 2006.

[332] Vargas, C., Ghilezan, M., Hollander, M., Gustafson, G., Korman, H., Gonzalez, J., et.al. A new model using number of needles and androgen deprivation to predict chronic urinary toxicity for high or low dose rate prostate brachytherapy, J Urol, 2005. 174(3): p. 882-887., http://www.ncbi.nlm.nih.gov/pubmed/16093980

[333] Grills, I.S., Martinez, A.A., Hollander, M., Huang, R., Goldman, K., Chen, P.Y., et.al. High dose rate brachytherapy as prostate cancer monotherapy reduces toxicity compared to low dose rate palladium seeds, J Urol, 2004. 171(3): p. 1098-1104., http://www.ncbi.nlm.nih.gov/pubmed/14767279