دليل سرطان البروستاتا

ia_gov_sa · guide · processed · 26 chunks

Review Article
Saudi Oncology Society and Saudi Urology Association combined clinical management guidelines for prostate cancer 2017
Ali Aljubran, Ashraf Abusamra \( ^{1} \) , Sultan Alkhateeb \( ^{2} \) , Mohammed Alotaibi \( ^{3} \) , Danny Rabah \( ^{4} \) , Shouki Bazarbashi, Hussain Alkushi \( ^{5} \) , Mubarak Al-Mansour \( ^{6} \) , Hulayel Alharbi \( ^{7} \) , Amin Eltijani \( ^{8} \) , Abdullah Alghamdi \( ^{9} \) , Abdullah Alsharm \( ^{10} \) , Imran Ahmad \( ^{11} \) , Esam Murshid \( ^{12} \)
Oncology Center, Section of Medical Oncology, King Faisal Specialist Hospital and Research Center, \( {}^{8} \) Department of Oncology, Division of Medical Oncology, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, \( {}^{9} \) Department of Urology, Prince Sultan Military Medical City, \( {}^{10} \) Department of Medical Oncology, Comprehensive Cancer Center, King Fahad Medical City, \( {}^{12} \) Department of Oncology, Oncology Center, Prince Sultan Military Medical City, \( {}^{1} \) Department of Surgery, Urology Section, King Abdulaziz Medical City, \( {}^{2} \) Department of Surgery, Division of Urology, King Abdulaziz Medical City and King Saud bin Abdulaziz University for Health Sciences, Riyadh, Departments of \( {}^{5} \) Pathology and \( {}^{6} \) Oncology, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, \( {}^{11} \) Department of Oncology, Section of Medical Oncology, King Faisal Specialist Hospital and Research Center, Jeddah, \( {}^{3} \) Department of Urology, King Faisal Specialist Hospital and Research Center, \( {}^{4} \) Department of Surgery, College of Medicine and Uro-Oncology Research Chair, King Saud University, \( {}^{7} \) Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, Saudi Arabia
Abstract
Keywords: Guidelines, management, prostate cancer, Saudi Oncology Society, Saudi Urological Association
Address for correspondence: Dr. Shouki Bazarabashi, Section of Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Center, P.O Box 3354, Riyadh - 11211, Saudi Arabia.
E-mail: bazarabshi@gmail.com
Received: 18.11.2017, Accepted: 18.12.2017
INTRODUCTION
In Saudi Arabia, prostate cancer is the sixth most common cancer among men of all ages. There were 310 cases of prostate cancer in 2001, accounting for 6.8% of all cancer
Access this article online
Quick Response Code:

Website:
www.urologyannals.com
DOI:
10.4103/UA.UA_177_17
cases among adult males in that year. The age-standardized rate (ASR) was 6.0/100,000. The five regions with the highest ASR were the Eastern region at 11.3/100,000, the Riyadh region at 8.0/100,000, the Makkah region at
For reprints contact: reprints@medknow.com
How to cite this article: Aljubran A, Abusamra A, Alkhateeb S, Alotaibi M, Rabah D, Bazarbashi S, et al. Saudi Oncology Society and Saudi Urology Association combined clinical management guidelines for prostate cancer 2017. Urol Ann 2018;10:138-45.
© 2018 Urology Annals | Published by Wolters Kluwer - Medknow

Aljubran, et al.: SOS and SUA guidelines for prostate cancer
5.9/100,000, the Northern region at 5.1/100,000, and the Asir region at 4.9/100,000. The median age at diagnosis was 72 years (range 6–101 years). The cancer stage at the time of diagnosis is localized in 46.9% of cases, with the remaining 53.1% being locally advanced (7.1%), metastatic (30.2%), or unknown (15.8%). \( ^{[1]} \) Notably, there has been a steady increase in the number of reported cases in the Saudi Cancer Registry for the last two decades, which could be secondary to wider prostate-specific antigen (PSA) utilization, improved documentation, and reporting.
The present guidelines are an update to the previously published Saudi Oncology Society guidelines for the evaluation, medical, and surgical management of prostate cancer. \( ^{[2-4]} \) More than 95% of primary prostate cancers are adenocarcinomas, so these guidelines are focused on this category of prostate tumors. This cancer is categorized according to the stage of the disease using the tumor node metastasis staging system \( 7^{th} \) edition. The guidelines are presented with supporting evidence level according to an article accompanying the guidelines \( 1^{st} \) edition, as well as the scope, purpose, and methods of these guidelines. \( ^{[5]} \)
DIAGNOSIS AND STAGING EVALUATION
When a biopsy is indicated, systematic transrectal ultrasound-guided core biopsies (10–12) should be performed. A multi-parametric magnetic resonance imaging (MRI)/ultrasound fusion-targeted biopsy may also be used, if available. Once the diagnosis is confirmed, the following staging evaluations should be done:
1. Computed tomography (CT) or MRI (abdomen and pelvis) should only be done when cancer is considered high risk according to D'Amico risk groups (EL-2) [Table 1] \( ^{[6,7]} \)
2. Bone scan should only be done if any of the following (EL-2): \( ^{[8-11]} \)
i. PSA level >20 ng/mL
ii. Patients with bone pain
iii. Gleason score ≥8
iv. Patient with clinical stage T3 or T4
v. Hypercalcemia or high serum alkaline phosphatase.
STAGING CLASSIFICATION
The tumor node metastasis AJCC staging \( 7^{th} \) edition should be used [Table 2].
Table 1: D'Amico risk groups for prostate cancer
<table><tr><td>Low-risk</td><td>Intermediate-risk</td><td>High-risk</td></tr><tr><td>T1-T2a and GS ≤6 and PSA ≤10</td><td>T2b and/or GS=7 and/or PSA &gt;10-20</td><td>≥ T2c or GS 8-10 or PSA &gt;20</td></tr></table>
PSA: Prostate-specific antigen, GS: Gleason score
MANAGEMENT
The management options for prostate adenocarcinoma depend on the stage (localized vs. metastatic), risk group, and life expectancy. \( ^{[12]} \) The approach to treatment is influenced by patient's age, general condition, and coexisting medical problems, as well as his preferences. Side effects of various forms of treatment should be considered in selecting appropriate management.
1. Localized disease (cT1-2 N0): Any benefits of definitive local therapy with curative intent may take years to emerge. Therefore, therapy with curative intent is usually reserved for men with a sufficiently long life expectancy
i. Low-risk – Therapy options depend on the following factors:
- If a patient is asymptomatic with life expectancy <5 years: No further intervention required until symptoms or clinical progression develops (EL-2) \( ^{[13-15]} \)
- If asymptomatic with life expectancy between 5 and 10 years: Active surveillance: involves active monitoring of the course of disease with the expectation to intervene with curative intent if cancer progresses (EL-2) \( ^{[13,15,16]} \)
- If asymptomatic with life expectancy >10 years: Options include active surveillance, radical prostatectomy (RP), external-beam radiation therapy (EBRT), or brachytherapy (EL-2) \( ^{[16-19]} \)
- The strategy behind active surveillance is to defer therapy for the clinically localized disease but regularly follow the patient and initiate local therapy with curative intent if there are any signs of local tumor progression. Active surveillance candidates must have all the following criteria: PSA <10 ng/ml, Gleason sum ≤6, number of positive cores ≤2, percentage of cancer involvement in any positive core <50%, and PSA density <0.15. Follow-up should entitle history, physical examination, and PSA every 3–6 months and repeated biopsy every 12–18 months (at least once); radical therapy should be offered if PSA velocity >0.35 ng/ml/year or progression in any of the aforementioned criteria \( ^{[20-24]} \)
- All RPs should be done in tertiary care centers by high-volume surgeons (EL-2); surgeon experience has been associated with improved recovery of postoperative continence and erectile function, with a very low surgical mortality \( ^{[25,26]} \)
- Lymph node dissection (LND) can be omitted if the chance of being positive is \(< 5\%\) according to nomograms (EL-2)\(^{[27,28]}\)
Urology Annals | Volume 10 | Issue 2 | April-June 2018

Aljubran, et al.: SOS and SUA guidelines for prostate cancer
Table 2: Tumor node metastasis stage definitions for prostate cancer
<table><tr><td>Primary tumor (T)</td><td>Regional lymph nodes (N)</td><td>Distant metastasis (M)§</td></tr><tr><td>TX: Primary tumor cannot be assessed</td><td>NX: Regional lymph node (s) were not assessedNO: No regional lymph node metastasis</td><td>M0: No distant metastasis</td></tr><tr><td>T0: No evidence of primary tumor</td><td>N1: Metastasis in regional lymph node (s)</td><td>M1: Distant metastasis or positive peritoneal cytologyM1a: Nonregional lymph node (s)</td></tr><tr><td>T1: Clinically inapparent tumor neither palpable nor visible by imaging</td><td></td><td></td></tr><tr><td>T1a: Tumor incidental histological finding in 5% or less of tissue resected</td><td></td><td>M1b: Bone (s)</td></tr><tr><td>T1b: Tumor incidental histological finding in more than 5% of tissue resected</td><td></td><td>M1c: Other site (s) with or without bone disease</td></tr><tr><td>T1c: Tumor identified by needle biopsy (e.g., because of elevated PSA)</td><td></td><td></td></tr><tr><td>T2: Tumor confined within prostate*</td><td></td><td></td></tr><tr><td>T2a: Tumor involves one-half of one lobe or less</td><td></td><td></td></tr><tr><td>T2b: Tumor involves more than one-half of one lobe but not both lobes</td><td></td><td></td></tr><tr><td>T2c: Tumor involves both lobes</td><td></td><td></td></tr><tr><td>T3: Tumor extends through the prostate capsule*</td><td></td><td></td></tr><tr><td>T3a: Extracapsular extension (unilateral or bilateral)</td><td></td><td></td></tr><tr><td>T3b: Tumor invades seminal vesicle (s)</td><td></td><td></td></tr><tr><td>T4: Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall</td><td></td><td></td></tr></table>
*Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c, #Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3 but as T2, §When more than one site of metastasis is present, the most advanced category is used. M1c is most advanced
- Intensity-modulated EBRT is the minimal standard of EBRT, in which the only acceptable biological dose is \(\geq 74\) Gy (EL-2).\(^{[29-31]}\)
ii. Intermediate risk – Therapy options depend on the following:
- If life expectancy is \(< 5\) years, a patient will have no further intervention until he becomes symptomatic or develops clinical progression (EL-2)\(^{[13,16]}\)
- If life expectancy is between 5 and 10 years, options include active surveillance,\(^{[9]}\) RP with LND as per nomograms,\(^{[32]}\) or EBRT with 6 months of androgen deprivation therapy (ADT) (EL-2)\(^{[33,34]}\)
- If life expectancy is >10 years, options are RP with LND (EL-1) \( ^{[35]} \) or EBRT with 6 months of ADT (EL-2) \( ^{[33,34]} \)
iii. High risk – Therapy options include EBRT (including pelvic lymph nodes and with or without brachytherapy boost) with ADT for 18 months \( ^{[36-43]} \) or RP with LND \( ^{[44,45]} \)
2. Locally advanced disease (cT3-4 or N1)
i. EBRT (including pelvic lymph nodes and with or without brachytherapy boost) with ADT for 2–3 years (EL-1) \( ^{[46-49]} \)
ii. RP with LND only if no clinical evidence of lymph node involvement and no tumor fixation (EL-3) \( ^{[44,45]} \)
iii. Patients who are unfit for the above-mentioned
two options may be candidates for deferred castration when PSA level exceeds 10–15 ng/ml (EL-2) \( ^{[50]} \)
3. Management after local therapy
i. RP patients who have pT3 (extraprostatic extension or seminal vesicle invasion), or positive margin with undetectable postoperative PSA, may undergo adjuvant EBRT to the prostatic bed (64–66 Gy) (EL-2) \( ^{[50-56]} \)
ii. Follow-up after curative therapy: Patients should have a disease-specific history, PSA at 3, 6, and 12 months after therapy, every 6 months for 3 years, and then annually (EL-3) \( ^{[57]} \)
4. Management of local recurrence after RP
i. Recurrence post-RP is defined by PSA level >0.2 ng/ml in two consecutive readings \( ^{[58-62]} \)
ii. After excluding metastases, treatment of local recurrence is early salvage EBRT, preferably with ADT for 6 months, to be started as early as possible when PSA value (<0.5 ng/ml) \( ^{[63-73]} \)
5. Management of local recurrence after EBRT
i. A PSA rise of 2 ng/mL above PSA nadir is the most reliable indication for recurrence (EL-2). \( ^{[74,75]} \) However, local recurrence is defined by the presence of all of the following: A positive prostatic biopsy 18 months or longer after EBRT associated with rise in PSA and no evidence of distant metastasis documented by CT scan or MRI and bone scan \( ^{[76,77]} \)
Urology Annals | Volume 10 | Issue 2 | April-June 2018

Aljubran, et al.: SOS and SUA guidelines for prostate cancer
ii. Options of therapy include ADT, which can be delayed up until a PSA result of 10 ng/ml or in carefully selected patients, \( ^{[78]} \) salvage prostatectomy or brachytherapy may be considered \( ^{[79,80]} \)
iii. Intermittent ADT for nonmetastatic relapse after EBRT is recommended (EL-1). \( ^{[81]} \) See item 6 below for intermittent ADT
6. Management of metastatic disease [Figure 1]
i. Castration-sensitive prostate cancer
- Chemohormonal therapy with six cycles of docetaxel and ADT is the standard of care (EL-1), \( ^{[82,83]} \) with the following considerations:
• Good performance status ECOG PS (0–1)
- Newly diagnosed cases (<120 days of preexisting ADT therapy)
- Prednisone 10 mg PO once daily is optional ADT options include bilateral orchiectomy (including subcapsular), luteinizing hormone-releasing hormone (LHRH) agonist, LHRH antagonists, and complete androgen blockade (CAB). \( ^{[84-87]} \) Intermittent or continuous ADT are appropriate options (EL-1) \( ^{[88-91]} \)
- In case of intermittent androgen blockade, the following should be observed:
- CAB (anti-androgen and LHRH) or LHRH antagonist should be used
- Initial induction cycle should last for 6–9 months
- Treatment is usually stopped only if the patient is compliant, showing good PSA response (PSA <4 ng/ml) in patients with metastatic disease and <0.5 ng/ml in biochemical relapse postlocal therapy, otherwise, should be on continuous ADT. PSA monitoring every 2–3 months is essential
• Therapy is re-instituted in cycles of 3–6 months if PSA reaches 10–15 ng/ml in
metastatic disease or 4 ng/ml if biochemical relapse occurs after local therapy
- When treating with LHRH agonists, a concomitant anti-androgen must be given during the initial 4 weeks to counteract the testosterone surge. Furthermore, this treatment should be preceded with 7–10 days of anti-androgen, in patients with impending cord compression or impending urinary outflow obstruction
- Preventive measures for metabolic, cardiovascular, and bone complications should be considered for patients on ADT. \( ^{[92,93]} \) See item 7 for bone health in prostate cancer
- In general, use of steroidal anti-androgens should be discouraged
- The care of patients should be coordinated through or taking place in hospitals with specialized oncology service
ii. Castration-resistant prostate cancer
- Defined as two consecutive rises in PSA in the testosterone level postcastration, which is <20 ng/dL (0.7 nmol/L), using early-morning samples \( ^{[94]} \)
- Treatment options for those who did not receive chemohormonal therapy include docetaxel with prednisone, abiraterone with prednisone, enzalutamide, and radium-223 (EL-1) \( ^{[95-98]} \)
- The treatment choice may depend on the following factors:
- For symptomatic patients and rapidly progressing disease: Docetaxel with prednisone
- For patients with no or mild symptoms and no visceral metastases: Abiraterone and prednisone

Figure 1: Algorithm for the management of advanced prostate cancer
Urology Annals | Volume 10 | Issue 2 | April-June 2018

Aljubran, et al.: SOS and SUA guidelines for prostate cancer
- For patients with no or mild symptoms: Enzalutamide
- For patients with only symptomatic bone metastases: Radium-223
- Treatment options for those who have progressed on or after docetaxel include cabazitaxel with prednisone, abiraterone with prednisone, enzalutamide, and radium-223[97,99-101]
- Cabazitaxel (20 mg every 3 weeks) with prednisone (10 mg OD) is an appropriate option for patients with rapidly progressing or symptomatic disease and still in good performance status (EL-1) \( ^{[102]} \)
• Patients with CRPC should continue ADT indefinitely.
7. Bone health in prostate cancer patients
i. All patients receiving any form of ADT should be prescribed Vitamin D (800 IU/day) and calcium supplements (1200 mg/day). Initial and periodic assessment of bone density and fracture risk may be beneficial in these patients. For patients at risk, (T-score < -1.5), treatment with either denosumab (60 mg every 6 months) or bisphosphonates can prevent bone loss associated with ADT \( ^{[92]} \)
ii. Patients with CRPC with bone metastases should receive rank-ligand antibodies (denosumab) therapy 120 mg every 4 weeks to reduce skeletal-related events (pathological fractures, bone radiation or surgery, and spinal cord compression) (EL-1). \( ^{[103]} \) However, when not available zoledronic acid can be given (EL-1). \( ^{[104]} \)
Financial support and sponsorship
Funding was provided by the Saudi Oncology Society for this work.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Saudi Cancer Registry. Annual Report; 2010. Available from: http://www.shc.gov.sa/Ar/HealthCenters/NCC/CancerRegistry/Pages/CancerRegistryRecords.aspx. [Last accessed on 2016 Oct 25].
2. Abusamra A, Murshid E, Kushi H, Alkhateeb S, Al-Mansour M, Saadeddin A, et al. Saudi oncology society and Saudi urology association combined clinical management guidelines for prostate cancer. Urol Ann 2016;8:123-30.
3. Abusamra AJ, Bazarbashi S, Bahader Y, Kushi H, Rabah D, Al Bogami N, et al. Saudi oncology society clinical management guidelines for prostate cancer. Urol Ann 2011;3 Suppl:S10-6.
4. Alkhateeb S, Abusamra A, Rabah D, Alotaibi M, Mahmood R, Almansour M, et al. Saudi oncology society and Saudi urology association combined clinical management guidelines for prostate
cancer. Urol Ann 2014;6:278-85.
5. Bazarbashi S. Why local guidelines? Urol Ann 2011;3 Suppl:S1-2.
6. Eifler JB, Feng Z, Lin BM, Partin MT, Humphreys EB, Han M, et al. An updated prostate cancer staging nomogram (Partin tables) based on cases from 2006 to 2011. BJU Int 2013;111:22-9.
7. Hövels AM, Heesakkers RA, Adang EM, Jager GJ, Strum S, Hoogeveen YL, et al. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: A meta-analysis. Clin Radiol 2008;63:387-95.
8. Huncharek M, Muscat J. Serum prostate-specific antigen as a predictor of radiographic staging studies in newly diagnosed prostate cancer. Cancer Invest 1995;13:31-5.
9. Kemp PM, Maguire GA, Bird NJ. Which patients with prostatic carcinoma require a staging bone scan? Br J Urol 1997;79:611-4.
10. Lee N, Fawaaz R, Olsson CA, Benson MC, Petrylak DP, Schiff PB, et al. Which patients with newly diagnosed prostate cancer need a radionuclide bone scan? An analysis based on 631 patients. Int J Radiat Oncol Biol Phys 2000;48:1443-6.
11. Oesterling JE, Martin SK, Bergstralh EJ, Lowe FC. The use of prostate-specific antigen in staging patients with newly diagnosed prostate cancer. JAMA 1993;269:57-60.
12. D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969-74.
13. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280:975-80.
14. Heidenreich A, Ohlmann CH, Polyakov S. Anatomical extent of pelvic lymphadenectomy in patients undergoing radical prostatectomy. Eur Urol 2007;52:29-37.
15. Klotz L. Active surveillance for prostate cancer: For whom? J Clin Oncol 2005;23:8165-9.
16. Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe C, Holding P, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 2016;375:1415-24.
17. Bill-Axelson A, Holmberg L, Garmo H, Rider JR, Taari K, Busch C, et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 2014;370:932-42.
18. Kupelian P, Kuban D, Thames H, Levy L, Horwitz E, Martinez A, et al. Improved biochemical relapse-free survival with increased external radiation doses in patients with localized prostate cancer: The combined experience of nine institutions in patients treated in 1994 and 1995. Int J Radiat Oncol Biol Phys 2005;61:415-9.
19. Potters L, Morgenstern C, Calugaru E, Fearn P, Jassal A, Presser J, et al. 12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer. J Urol 2005;173:1562-6.
20. Dall'Era MA, Albertsen PC, Bangma C, Carroll PR, Carter HB, Cooperberg MR, et al. Active surveillance for prostate cancer: A systematic review of the literature. Eur Urol 2012;62:976-83.
21. Sanda MG, Dunn RL, Michalski J, Sandler HM, Northouse L, Hembroff L, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358:1250-61.
22. Thomsen FB, Brasso K, Klotz LH, Røder MA, Berg KD, Iversen P, et al. Active surveillance for clinically localized prostate cancer – A systematic review. J Surg Oncol 2014;109:830-5.
23. Tosoian JJ, Trock BJ, Landis P, Feng Z, Epstein JI, Partin AW, et al. Active surveillance program for prostate cancer: An update of the Johns Hopkins experience. J Clin Oncol 2011;29:2185-90.
24. van den Bergh RC, Roemeling S, Roobol MJ, Aus G, Hugosson J, Rannikko AS, et al. Outcomes of men with screen-detected prostate cancer eligible for active surveillance who were managed expectantly. Eur Urol 2009;55:1-8.
25. Eastham JA, Kattan MW, Riedel E, Begg CB, Wheeler TM, Gerigk C, et al. Variations among individual surgeons in the rate of
Urology Annals | Volume 10 | Issue 2 | April-June 2018

Aljubran, et al.: SOS and SUA guidelines for prostate cancer
positive surgical margins in radical prostatectomy specimens. J Urol 2003;170:2292-5.
26. Gore JL, Wright JL, Daratha KB, Roberts KP, Lin DW, Wessells H, et al. Hospital-level variation in the quality of urologic cancer surgery. Cancer 2012;118:987-96.
27. Briganti A, Chun FK, Salonia A, Zanni G, Gallina A, Dehò F, et al. A nomogram for staging of exclusive nonobturator lymph node metastases in men with localized prostate cancer. Eur Urol 2007;51:112-9.
28. Cagiannos I, Karakiewicz P, Eastham JA, Ohori M, Rabbani F, Gerigk C, et al. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J Urol 2003;170:1798-803.
29. Kuban DA, Levy LB, Cheung MR, Lee AK, Choi S, Frank S, et al. Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease? Int J Radiat Oncol Biol Phys 2011;79:1310-7.
30. Spratt DE, Pei X, Yamada J, Kollmeier MA, Cox B, Zelefsky MJ, et al. Long-term survival and toxicity in patients treated with high-dose intensity modulated radiation therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2013;85:686-92.
31. Zietman AL, DeSilvio ML, Slater JD, Rossi CJ Jr., Miller DW, Adams JA, et al. Comparison of conventional-dose vs. high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: A randomized controlled trial. JAMA 2005;294:1233-9.
32. D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW, et al. 6-month androgen suppression plus radiation therapy vs. radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial. JAMA 2004;292:821-7.
33. Toren P, Wong LM, Timilshina N, Alibhai S, Trachtenberg J, Fleshner N, et al. Active surveillance in patients with a PSA >10 ng/mL. Can Urol Assoc J 2014;8:E702-7.
34. Zumsteg ZS, Spratt DE, Pei X, Yamada Y, Kalikstein A, Kuk D, et al. Short-term androgen-deprivation therapy improves prostate cancer-specific mortality in intermediate-risk prostate cancer patients undergoing dose-escalated external beam radiation therapy. Int J Radiat Oncol Biol Phys 2013;85:1012-7.
35. Pollack A, Zagars GK, Smith LG, Lee JJ, von Eschenbach AC, Antolak JA, et al. Preliminary results of a randomized radiotherapy dose-escalation study comparing 70 gy with 78 gy for prostate cancer. J Clin Oncol 2000;18:3904-11.
36. Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomised trial. Lancet 2002;360:103-6.
37. Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295-300.
38. Bolla M, Van Tienhoven G, Warde P, Dubois JB, Mirimanoff RO, Storme G, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010;11:1066-73.
39. Cuppone F, Bria E, Giannarelli D, Vaccaro V, Milella M, Nisticò C, et al. Impact of hormonal treatment duration in combination with radiotherapy for locally advanced prostate cancer: Meta-analysis of randomized trials. BMC Cancer 2010;10:675.
40. Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, et al. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The radiation therapy oncology group protocol 92-02. J Clin Oncol 2003;21:3972-8.
41. Nabid A. Long-term quality of life in high-risk prostate cancer: Results of a phase III randomized trial. J Clin Oncol 2014;32 (Suppl 4; abstr 5).
42. Pollack A, Zagars GK, Starkschall G, Antolak JA, Lee JJ, Huang E, et al. Prostate cancer radiation dose response: Results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53:1097-105.
43. Schmidt-Hansen M, Hoskin P, Kirkbride P, Hasler E, Bromham N. Hormone and radiotherapy versus hormone or radiotherapy alone for non-metastatic prostate cancer: A systematic review with meta-analyses. Clin Oncol (R Coll Radiol) 2014;26:e21-46.
44. Lau WK, Bergstralh EJ, Blute ML, Slezak JM, Zincke H. Radical prostatectomy for pathological Gleason 8 or greater prostate cancer: Influence of concomitant pathological variables. J Urol 2002;167:117-22.
45. Studer UE, Whelan P, Albrecht W, Casselman J, de Reijke T, Hauri D, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European organisation for research and treatment of cancer (EORTC) trial 30891. J Clin Oncol 2006;24:1868-76.
46. Nabid A, Carrier N, Martin AG, Bahary JP, Souhami L, Duclos M, et al. High-Risk Prostate Cancer Treated with Pelvic Radiotherapy and 36 Versus 18 Months of Androgen Blockade: Results of a Phase III Randomized Study. 2013, American Society of Clinical Oncology; 2013.
47. Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, et al. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation advantage to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;50:1243-52.
48. Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma – Long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61:1285-90.
49. Yossepowitch O, Eggener SE, Bianco FJ Jr., Carver BS, Serio A, Scardino PT, et al. Radical prostatectomy for clinically localized, high risk prostate cancer: Critical analysis of risk assessment methods. J Urol 2007;178:493-9.
50. Bolla M, van Poppel H, Tombal B, Vekemans K, Da Pozzo L, de Reijke TM, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: Long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012;380:2018-27.
51. Chen C, Lin T, Zhou Y, Li D, Xu K, Li Z, et al. Adjuvant and salvage radiotherapy after prostatectomy: A systematic review and meta-analysis. PLoS One 2014;9:e104918.
52. Daly T, Hickey BE, Lehman M, Francis DP, See AM. Adjuvant radiotherapy following radical prostatectomy for prostate cancer. Cochrane Database Syst Rev 2011;(12):CD007234.
53. Swanson G, Thompson I, Tangen C, Paradelo J, Canby-Hagino E, Crawford E, et al. Update of swog 8794: Adjuvant radiotherapy for pt3 prostate cancer improves metastasis free survival. Int J Radiat Oncol Biol Phys 2008;72:S31.
54. Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: Long-term followup of a randomized clinical trial. J Urol 2009;181:956-62.
55. Van der Kwast TH, Bolla M, Van Poppel H, Van Cangh P, Vekemans K, Da Pozzo L, et al. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007;25:4178-86.
56. Wiegel T, Bartkowiak D, Bottke D, Bronner C, Steiner U, Siegmann A, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol 2014;66:243-50.
57. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591-7.
Urology Annals | Volume 10 | Issue 2 | April-June 2018

Aljubran, et al.: SOS and SUA guidelines for prostate cancer
58. Boccon-Gibod L, Djavan WB, Hammerer P, Hoeltl W, Kattan MW, Prayer-Galetti T, et al. Management of prostate-specific antigen relapse in prostate cancer: A European consensus. Int J Clin Pract 2004;58:382-90.
59. Cheung R, Kamat AM, de Crevoisier R, Allen PK, Lee AK, Tucker SL, et al. Outcome of salvage radiotherapy for biochemical failure after radical prostatectomy with or without hormonal therapy. Int J Radiat Oncol Biol Phys 2005;63:134-40.
60. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol 2000;163:1632-42.
61. Stephenson AJ, Scardino PT, Kattan MW, Pisansky TM, Slawin KM, Klein EA, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035-41.
62. Wiegel T, Lohm G, Bottke D, Höcht S, Miller K, Siegmann A, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome – results of a retrospective study. Int J Radiat Oncol Biol Phys 2009;73:1009-16.
63. Cox JD, Grignon DJ, Kaplan RS, Parsons JT, Schellhammer PF. Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997;37:1035-41.
64. King CR. The timing of salvage radiotherapy after radical prostatectomy: A systematic review. Int J Radiat Oncol Biol Phys 2012;84:104-11.
65. Kunath F, Keck B, Rücker G, Motschall E, Wullich B, Antes G, et al. Early versus deferred androgen suppression therapy for patients with lymph node-positive prostate cancer after local therapy with curative intent: A systematic review. BMC Cancer 2013;13:131.
66. Lee AK, D'Amico AV. Utility of prostate-specific antigen kinetics in addition to clinical factors in the selection of patients for salvage local therapy. J Clin Oncol 2005;23:8192-7.
67. Ost P, Lumen N, Goessaert AS, Fonteyne V, De Troyer B, Jacobs F, et al. High-dose salvage intensity-modulated radiotherapy with or without androgen deprivation after radical prostatectomy for rising or persisting prostate-specific antigen: 5-year results. Eur Urol 2011;60:842-9.
68. Parekh A, Chen MH, Graham P, Mahal BA, Hirsch AE, Nakabayashi M, et al. Role of androgen deprivation therapy in early salvage radiation among patients with prostate-specific antigen level of 0.5 or less. Clin Genitourin Cancer 2015;13:e1-6.
69. Patel R, Lepor H, Thiel RP, Taneja SS. Prostate-specific antigen velocity accurately predicts response to salvage radiotherapy in men with biochemical relapse after radical prostatectomy. Urology 2005;65:942-6.
70. Ploussard G, Staerman F, Pierrevelcin J, Larue S, Villers A, Ouzzane A, et al. Clinical outcomes after salvage radiotherapy without androgen deprivation therapy in patients with persistently detectable PSA after radical prostatectomy: Results from a national multicentre study. World J Urol 2014;32:1331-8.
71. Stephenson AJ, Shariat SF, Zelefsky MJ, Kattan MW, Butler EB, Teh BS, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004;291:1325-32.
72. Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, et al. Prostate cancer-specific survival following salvage radiotherapy vs. observation in men with biochemical recurrence after radical prostatectomy. JAMA 2008;299:2760-9.
73. Ward JF, Zincke H, Bergstralh EJ, Slezak JM, Blute ML. Prostate specific antigen doubling time subsequent to radical prostatectomy as a prognosticator of outcome following salvage radiotherapy. J Urol 2004;172:2244-8.
74. Cox JD, Gallagher MJ, Hammond EH, Kaplan RS, Schellhammer PF. Consensus statements on radiation therapy of prostate cancer: Guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. American Society for Therapeutic Radiology and Oncology Consensus Panel. J Clin Oncol 1999;17:1155.
75. Roach M 3 \( ^{rd} \) , Hanks G, Thames H Jr., Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO phoenix consensus conference. Int J Radiat Oncol Biol Phys 2006;65:965-74.
76. Pinover WH, Horwitz EM, Hanlon AL, Uzzo RG, Hanks GE. Validation of a treatment policy for patients with prostate specific antigen failure after three-dimensional conformal prostate radiation therapy. Cancer 2003;97:1127-33.
77. Taylor JM, Griffith KA, Sandler HM. Definitions of biochemical failure in prostate cancer following radiation therapy. Int J Radiat Oncol Biol Phys 2001;50:1212-9.
78. Burri RJ, Stone NN, Unger P, Stock RG. Long-term outcome and toxicity of salvage brachytherapy for local failure after initial radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2010;77:1338-44.
79. Moman MR, van der Poel HG, Battermann JJ, Moerland MA, van Vulpen M. Treatment outcome and toxicity after salvage 125-I implantation for prostate cancer recurrences after primary 125-I implantation and external beam radiotherapy. Brachytherapy 2010;9:119-25.
80. Seidenfeld J, Samson DJ, Hasselblad V, Aronson N, Albertsen PC, Bennett CL, et al. Single-therapy androgen suppression in men with advanced prostate cancer: A systematic review and meta-analysis. Ann Intern Med 2000;132:566-77.
81. Crook JM, O'Callaghan CJ, Duncan G, Dearnaley DP, Higano CS, Horwitz EM, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med 2012;367:895-903.
82. James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387:1163-77.
83. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015;373:737-46.
84. Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, et al. The efficacy and safety of degarelix: A 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int 2008;102:1531-8.
85. Klotz L, Miller K, Crawford ED, Shore N, Tombal B, Karup C, et al. Disease control outcomes from analysis of pooled individual patient data from five comparative randomised clinical trials of degarelix versus luteinising hormone-releasing hormone agonists. Eur Urol 2014;66:1101-8.
86. Samson DJ, Seidenfeld J, Schmitt B, Hasselblad V, Albertsen PC, Bennett CL, et al. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer 2002;95:361-76.
87. Tombal B, Damber JE, Malmberg A, Persson BE, Klotz L, Iversen P. Degarelix Monotherapy Versus Luteinizing Hormone-Releasing Hormone (lhrh) Agonists Plus Antiandrogen Flare Protection in the Treatment of Men with Advanced Prostate Cancer. 2014, American Society of Clinical Oncology; 2014.
88. Botrel TE, Clark O, dos Reis RB, Pompeo AC, Ferreira U, Sadi MV, et al. Intermittent versus continuous androgen deprivation for locally advanced, recurrent or metastatic prostate cancer: A systematic review and meta-analysis. BMC Urol 2014;14:9.
89. Hussain M, Tangen CM, Berry DI, Higano CS, Crawford ED, Liu G, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med 2013;368:1314-25.
90. Magnan S, Zarychanski R, Pilote L, Bernier L, Shemilt M, Vigneault E, et al. Intermittent vs. continuous androgen deprivation therapy for prostate cancer: A systematic review and meta-analysis. JAMA Oncol 2015;1:1261-9.
91. Niraula S, Le LW, Tannock IF. Treatment of prostate cancer with
Urology Annals | Volume 10 | Issue 2 | April-June 2018

Aljubran, et al.: SOS and SUA guidelines for prostate cancer
intermittent versus continuous androgen deprivation: A systematic review of randomized trials. J Clin Oncol 2013;31:2029-36.
92. Grossmann M, Zajac JD. Androgen deprivation therapy in men with prostate cancer: How should the side effects be monitored and treated? Clin Endocrinol (Oxf) 2011;74:289-93.
93. National Osteoporosis Foundation. National Osteoporosis Foundation Clinician's Guide to Prevention and Treatment of Osteoporosis; 2013. Available from: http://www.nof.org/professionals/clinical-guidelines. [Last accessed on 2014 Mar 05].
94. Oefelein MG, Feng A, Scolieri MJ, Ricchiutti D, Resnick MI. Reassessment of the definition of castrate levels of testosterone: Implications for clinical decision making. Urology 2000;56:1021-4.
95. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424-33.
96. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the tax 327 study. J Clin Oncol 2008;26:242-5.
97. Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369:213-23.
98. Ryan CJ, Smith MR, De Bono JS, Molina A, Logothetis C, De Souza PL, et al. Interim Analysis (ia) Results of cou-aa-302, a Randomized, Phase iii Study of Abiraterone Acetate (aa) in Chemotherapy-Naive Patients (pts) with Metastatic Castration-Resistant Prostate Cancer (MCRPC). 2012, American Society of Clinical Oncology; 2012.
99. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet 2010;376:1147-54.
100. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: Final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012;13:983-92.
101. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187-97.
102. De Bono JS, Hardy-Bessard AC, Kim CS, Geczi L, Ford D, Mourey L, et al. Phase iii Non-Inferiority Study of Cabazitaxel (c) 20 mg/m2 (c20) Versus 25 mg/m2 (c25) in Patients (pts) with Metastatic Castration-Resistant Prostate Cancer (MCRPC) Previously Treated with Docetaxel (d). 2016, American Society of Clinical Oncology; 2016.
103. Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study. Lancet 2011;377:813-22.
104. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879-82.
Urology Annals | Volume 10 | Issue 2 | April-June 2018