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A systematic review of contemporary management of oligometastatic prostate cancer: fighting a challenge or tilting at windmills?

  • Amine SlaouiEmail author
  • S. Albisinni
  • F. Aoun
  • G. Assenmacher
  • W. Al Hajj Obeid
  • R. Diamand
  • S. Regragui
  • A. Touzani
  • A. Bakar
  • A. Mesfioui
  • T. Karmouni
  • A. Ameur
  • K. Elkhader
  • A. Koutani
  • A. Ibnattya
  • T. Roumeguere
  • A. Peltier
Original Article

Abstract

Purpose

Amongst the unanswered questions regarding prostate cancer (PCa), the optimal management of oligometastatic disease remains one of the major concerns of the scientific community. The very existence of this category is still subject to controversy. Aim of this systematic review is to summarize current available data on the most appropriate management of oligometastatic PCa.

Evidence acquisition

All relevant studies published in English up to November the 1st were identified through systematic searches in PubMed, EMBASE, Cochrane Library, CINAHL, Google Scholar and Ovid database. A search was performed including the combination of following words: (prostate cancer) and (metastatic) and [(oligo) or (PSMA) or (cytoreductive) or (stereotaxic radiotherapy) or (prostatectomy)]. 3335 articles were reviewed. After title screening and abstract reading, 118 papers were considered for full reading, leaving a total of 36 articles for the systematic review.

Evidence synthesis

There is still no consensus on the definition of oligometastatic disease, nor on the imaging modalities used for its detection. While retrospective studies suggest an added benefit with the treatment the primitive tumor by cytoreductive prostatectomy (55% survival rate vs 21%, p < 0.001), prospective studies do not validate the same outcome. Nonetheless, most studies have reported a reduction in local complications after cytoreductive prostatectomy (< 10%) compared to the best systemic treatment (25–30%). Concerning radiotherapy, an overall survival benefit for patients with a low metastatic burden was found in STAMPEDE (HR 0.68, 95% CI 0.52–0.90; p = 0.007) and suggested in subgroup analysis of the HORRAD trial. Regarding the impact of metastases-directed therapy (MDT), the STOMP and ORIOLE trials suggested that metastatic disease control might improve androgen deprivation therapy-free survival (in STOMP: 21 vs 13 months for MDT vs standard of care). Nonetheless, the impact of MDT on long-term oncologic results remains unclear. Finally, oligometastatic disease appears to be a biologically different entity compared to high-burden metastatic disease. New findings on exosomes appear to make them intriguing biomarkers in the early phases of oligometastatic PCa.

Conclusion

Oligometastatic PCa is today a poorly understood disease. The implementation of new imaging techniques as whole-body MRI and PSMA PET/CT has increased exponentially the number of oligometastatic patients detected. Data of available trials suggest a benefit from cytoreductive prostatectomy to reduce local complication, though its impact on survival remains unknown. Radiotherapy may be beneficial for patients with low-burden metastatic PCa, while MDT may delay the need for androgen deprivation therapy. Results from ongoing trials data are eagerly awaited to draw reliable recommendations.

Keywords

Prostate Cancer Oligometastatic Cytoreductive surgery Radiotherapy Metastasis-directed therapies 

Abreviations

ADT

Androgen deprivation therapy

CT

Computed tomography

EBRT

External beam radiation therapy

HR

Hazard ratio

ICECaP

Intermediate clinical criteria in prostate cancer

MDT

Metastasis-directed therapy

MRI

Magnetic resonance imaging

M0

Nonmetastatic

PCa

Prostate cancer

PICOS

Population, intervention, comparator, outcome and study design

PRISMA

Preferred reporting items for systematic reviews and meta analyses

RP

Radical prostatectomy

SBRT

Stereotactic body radiotherapy

99mTc-MDP

99mTechnetium-methylene diphosphonate

Notes

Author contributions

AS: project development, data collection, data analysis, manuscript writing. SA: project development, data collection, data analysis, manuscript writing. FA: project development, data analysis, manuscript writing. GA: project development, data analysis. WAHO: data collection. RD: data analysis, manuscript writing. SR: data collection. AT: data collection. AB: data collection. AM: project development. TK: project development, data analysis, manuscript writing. AA: project development, data analysis, manuscript writing. KE: project development, data analysis, manuscript writing. AK: project development, data analysis, manuscript writing. AI: project development, data analysis, manuscript writing. TR: project development, data analysis, manuscript writing. AP: project development, data analysis, manuscript writing.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Kelly SP, Anderson WF, Rosenberg PS, Cook MB (2018) Past, current, and future incidence rates and burden of metastatic prostate cancer in the United States. Eur Urol Focus 4(1):121–127CrossRefGoogle Scholar
  2. 2.
    Angela Culhane A (2017) Cancer research UK prostate cancer mortality statistics. Cancer Research UK, LondonGoogle Scholar
  3. 3.
    Corfield J, Perera M, Bolton D et al (2018) 68 Ga-prostate specific membrane antigen (PSMA) positron emission tomography (PET) for primary staging of high-risk prostate cancer: a systematic review. World J Urol 36:519CrossRefGoogle Scholar
  4. 4.
    Tosoian JJ, Gorin MA, Ross AE, Pienta KJ, Tran PT, Schaeffer EM (2017) Oligometastatic prostate cancer: definitions, clinical outcomes, and treatment considerations. Nat Rev Urol 14:15–25CrossRefGoogle Scholar
  5. 5.
    Hoyle AP, Ali SA, James ND et al (2018) Effects of abiraterone acetate plus prednisone/prednisolone in high and low risk metastatic hormone sensitive prostate cancer. Ann Oncol 29(Suppl 8):mdy424.033Google Scholar
  6. 6.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700.  https://doi.org/10.1136/bmj.b2700 CrossRefGoogle Scholar
  7. 7.
    Hellman S, Weichselbaum RR (1995) Oligometastases. J Clin Oncol 13:8–10CrossRefGoogle Scholar
  8. 8.
    Reyes DK, Pienta KJ (2015) The biology and treatment of oligometastatic cancer. Oncotarget 6(11):8491–8524CrossRefGoogle Scholar
  9. 9.
    Gillessen S, Attard G, Beer TM et al (2018) Management of patients with advanced prostate cancer: the report of the advanced prostate cancer consensus conference APCCC 2017. Eur Urol 73:178–211CrossRefGoogle Scholar
  10. 10.
    Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M, Fossati N, Gross T, Henry AM, Joniau S, Lam TB, Mason MD, Matveev VB, Moldovan PC, van den Bergh RC, Van den Broeck T, van der Poel HG, van der Kwast TH, Rouvière O, Schoots IG, Wiegel T, Cornford P (2017) EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol 71(4):618–629CrossRefGoogle Scholar
  11. 11.
    Rowe SP, Mana-Ay M, Javadi MS, Szabo Z, Leal JP, Pomper MG, Pienta KJ, Ross AE, Gorin MA (2016) PSMA-based detection of prostate cancer bone lesions with F-DCFPyL PET/CT: a sensitive alternative to Tc-MDP bone scan and NaF PET/CT? Clin Genitourin Cancer 14:115–118CrossRefGoogle Scholar
  12. 12.
    Sterzing F, Kratochwil C, Fiedler H, Katayama S, Habl G, Kopka K, Afshar-Oromieh A, Debus J, Haberkorn U, Giesel FL (2016) (68)Ga-PSMA-11 PET/CT: a new technique with high potential for the radiotherapeutic management of prostate cancer patients. Eur J Nucl Med Mol Imaging 43(1):34–41CrossRefGoogle Scholar
  13. 13.
    Perera M, Papa N, Christidis D, Wetherell D, Hofman MS, Murphy DG, Bolton D, Lawrentschuk N (2016) Sensitivity, specificity, and predictors of positive 68 Ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. Eur Urol 70:926–937CrossRefGoogle Scholar
  14. 14.
    Albisinni S, Artigas C, Aoun F, Biaou I, Grosman J, Gil T, Hawaux E, Limani K, Otte FX, Peltier A, Sideris S, Sirtaine N, Flamen P, Van Velthoven R (2017) Clinical impact of 68 Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer with rising prostate-specific antigen after treatment with curative intent: preliminary analysis of a multidisciplinary approach. BJU Int. 120(2):197–203CrossRefGoogle Scholar
  15. 15.
    Roach PJ, Francis R, Emmett L, Hsiao E, Kneebone A, Hruby G, Eade T, Nguyen QA, Thompson BD, Cusick T, McCarthy M, Tang C, Ho B, Stricker PD, Scott AM (2018) The Impact of 68 Ga-PSMA PET/CT on management intent in prostate cancer: results of an Australian prospective multicenter study. J Nucl Med 59(1):82–88CrossRefGoogle Scholar
  16. 16.
    Murphy DG, Sweeney CJ, Tombal B (2017) “Gotta catch ‘em all”, or do we? Pokemet approach to metastatic prostate cancer. Eur Urol 72(1):1–3CrossRefGoogle Scholar
  17. 17.
    Mole RH (1953) Whole body irradiation; radiobiology or medicine? Br J Radiol 26(305):234–241CrossRefGoogle Scholar
  18. 18.
    Powell IJ, Tangen CM, Miller GJ, Lowe BA, Haas G, Carroll PR et al (2002) Neoadjuvant therapy before radical prostatectomy for clinical T3/T4 carcinoma of the prostate: 5-year followup, phase II Southwest Oncology Group Study 9109. J Urol 168(5):2016–2019CrossRefGoogle Scholar
  19. 19.
    Chi KN, Chin JL, Winquist E, Klotz L, Saad F, Gleave ME (2008) Multicenter phase II study of combined neoadjuvant docetaxel and hormone therapy before radical prostatectomy for patients with high risk localized prostate cancer. J Urol 180(2):565–570 (discussion 570) CrossRefGoogle Scholar
  20. 20.
    Taplin M-E, Montgomery B, Logothetis CJ, Bubley GJ, Richie JP, Dalkin BL et al (2014) Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study. J Clin Oncol 32(33):3705–3715CrossRefGoogle Scholar
  21. 21.
    Ross RW, Galsky MD, Febbo P, Barry M, Richie JP, Xie W et al (2012) Phase 2 study of neoadjuvant docetaxel plus bevacizumab in patients with high-risk localized prostate cancer: a Prostate Cancer Clinical Trials Consortium trial. Cancer 118(19):4777–4784CrossRefGoogle Scholar
  22. 22.
    Nesseler JP, Peiffert D, Vogin G, Nickers P (2017) Cancer, radiotherapy and immune system. Cancer Radiother 21(4):307–315CrossRefGoogle Scholar
  23. 23.
    Tzelepi V, Efstathiou E, Wen S, Troncoso P, Karlou M, Pettaway CA, Pisters LL, Hoang A, Logothetis CJ, Pagliaro LC (2011) Persistent, biologically meaningful prostate cancer after 1 year of androgen ablation and docetaxel treatment. J Clin Oncol 29(18):2574–2581CrossRefGoogle Scholar
  24. 24.
    Zelefsky MJ, Reuter VE, Fuks Z, Scardino P (2008) Shippy A Influence of local tumor control on distant metastases and cancer related mortality after external beam radiotherapy for prostate cancer. J Urol 179(4):1368–1373   CrossRefGoogle Scholar
  25. 25.
    Comen E, Norton L, Massagué J (2011) Clinical implications of cancer self-seeding. Nat Rev Clin Oncol 8(6):369–377CrossRefGoogle Scholar
  26. 26.
    Pienta KJ, Robertson BA, Coffey DS, Taichman RS (2013) The cancer diaspora: metastasis beyond the seed and soil hypothesis. Clin Cancer Res 19:5849–5855CrossRefGoogle Scholar
  27. 27.
    Haffner MC, Mosbruger T, Esopi DM et al (2013) Tracking the clonal origin of lethal prostate cancer. J Clin Investig 123(11):4918–4922CrossRefGoogle Scholar
  28. 28.
    Folkersma LR, Manso LSJ, Romo IG, Sierra JM, Gómez CO (2012) Prognostic significance of circulating tumor cell count in patients with metastatic hormone-sensitive prostate cancer. Urology 80(6):1328–1332CrossRefGoogle Scholar
  29. 29.
    Fisher B, Gunduz N, Coyle J, Rudock C, Saffer E (1989) Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Can Res 49(8):1996–2001Google Scholar
  30. 30.
    Naumov GN, Folkman J, Straume O, Akslen LA (2008) Tumor-vascular interactions and tumor dormancy. APMIS. 116(7–8):569–585CrossRefGoogle Scholar
  31. 31.
    Gratzke C, Engel J, Stief CG (2014) Role of radical prostatectomy in metastatic prostate cancer: data from the Munich Cancer Registry. Eur Urol 66:602–603CrossRefGoogle Scholar
  32. 32.
    Antwi S, Everson TM (2014) Prognostic impact of definitive local therapy of the primary tumor in men with metastatic prostate cancer at diagnosis: a population-based, propensity score analysis. Cancer Epidemiol 38:435–441CrossRefGoogle Scholar
  33. 33.
    Culp SH, Schellhammer PF, Williams MB (2014) Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol. 65:1058–1066CrossRefGoogle Scholar
  34. 34.
    Engel J, Bastian PJ, Baur H et al (2010) Survival benefit of radical prostatectomy in lymph node-positive patients with prostate cancer. Eur Urol 57:754–761CrossRefGoogle Scholar
  35. 35.
    Heidenreich A, Pfister D, Porres D (2015) Cytoreductive radical prostatectomy in patients with prostate cancer and low volume skeletal metastases: results of a feasibility and case-control study. J Urol 193:832–838CrossRefGoogle Scholar
  36. 36.
    Sooriakumaran P, Karnes J, Stief C et al (2016) A multi-institutional analysis of perioperative outcomes in 106 men who underwent radical prostatectomy for distant metastatic prostate cancer at presentation. Eur Urol 69:788–794CrossRefGoogle Scholar
  37. 37.
    Rusthoven CG, Jones BL, Flaig TW et al (2016) Improved survival with prostate radiation in addition to androgen deprivation therapy for men with newly diagnosed metastatic prostate cancer. J Clin Oncol 34:2835–2842CrossRefGoogle Scholar
  38. 38.
    Steuber T, Berg KD, Røder MA et al (2017) Does cytoreductive prostatectomy really have an impact on prognosis in prostate cancer patients with low-volume bone metastasis? results from a prospective case-control study. Eur Urol Focus. 3:646–649CrossRefGoogle Scholar
  39. 39.
    Preisser F, Mazzone E, Nazzani S, Bandini M, Tian Z, Marchioni M, Steuber T, Saad F, Montorsi F, Shariat SF, Huland H, Graefen M, Tilki D, Karakiewicz PI (2018) Comparison of perioperative outcomes between cytoreductive radical prostatectomy and radical prostatectomy for nonmetastatic prostate cancer. Eur Urol 74(6):693–696CrossRefGoogle Scholar
  40. 40.
    Won AC, Gurney H, Marx G, De Souza P, Patel MI (2013) Primary treatment of the prostate improves local palliation in men who ultimately develop castrate-resistant prostate cancer. BJU Int. 112:E250–E255.  https://doi.org/10.1111/bju.12169 CrossRefGoogle Scholar
  41. 41.
    Albisinni S, Aoun F, Diamand R, Al-Hajj Obeid W, Porpiglia F, Roumeguere T, De Nunzio C (2018) Cytoreductive prostatectomy: what is the evidence? A systematic review. Minerva Urol Nefrol.  https://doi.org/10.23736/S0393-2249.18.03319-2 Google Scholar
  42. 42.
    Löppenberg B, Dalela D, Karabon P, Sood A, Sammon JD, Meyer CP, Sun M, Noldus J, Peabody JO, Trinh QD, Menon M, Abdollah F (2017) The impact of local treatment on overall survival in patients with metastatic prostate cancer on diagnosis: a national cancer data base analysis. Eur Urol 72(1):14–19CrossRefGoogle Scholar
  43. 43.
    Boevé LMS, Hulshof MCCM, Vis AN, Zwinderman AH, Twisk JWR, Witjes WPJ, Delaere KPJ, Moorselaar RJAV, Verhagen PCMS, van Andel G (2018) Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD trial. Eur Urol.  https://doi.org/10.1016/j.eururo.2018.09.008 Google Scholar
  44. 44.
    Parker CC, James ND, Brawley CD, Clarke NW, Hoyle AP, Ali A, Ritchie AWS, Attard G, Chowdhury S, Cross W, Dearnaley DP, Gillessen S, Gilson C, Jones RJ, Langley RE, Malik ZI, Mason MD, Matheson D, Millman R, Russell JM, Thalmann GN, Amos CL, Alonzi R, Bahl A, Birtle A, Din O, Douis H, Eswar C, Gale J, Gannon MR, Jonnada S, Khaksar S, Lester JF, O’Sullivan JM, Parikh OA, Pedley ID, Pudney DM, Sheehan DJ, Srihari NN, Tran ATH, Parmar MKB, Sydes MR, Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators (2018) Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet 392(10162):2353–2366CrossRefGoogle Scholar
  45. 45.
    Ost P, Bossi A, Decaestecker K, De Meerleer G, Giannarini G, Karnes RJ, Roach M 3rd, Briganti A (2015) Metastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. Eur Urol 67:852–863CrossRefGoogle Scholar
  46. 46.
    De Bleser E, Tran PT, Ost P (2017) Radiotherapy as metastasis-directed therapy for oligometastatic prostate cancer. Curr Opin Urol. 27(6):587–595CrossRefGoogle Scholar
  47. 47.
    Ost P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, De Bruycker A, Lambert B, Delrue L, Bultijnck R, Claeys T, Goetghebeur E, Villeirs G, De Man K, Ameye F, Billiet I, Joniau S, Vanhaverbeke F, De Meerleer G (2018) Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol 36(5):446–453CrossRefGoogle Scholar
  48. 48.
    Radwan N, Pillips R, Ross A, Rowe SP, Gorin MA, Antonarakis ES, Deville C, Greco S, Denmeade S, Paller C, Song DY, Diehn M, Wang H, Carducci M, Pienta KJ, Pomper MG, DeWeese TL, Dicker A, Eisenberger M, Tran PT (2017) A phase II randomized trial of observation versus stereotactic ablative radiation for oligometastatic prostate CancEr (ORIOLE). BMC Cancer 17(1):453.  https://doi.org/10.1186/s12885-017-3455-6 CrossRefGoogle Scholar
  49. 49.
    Montorsi F, Gandaglia G, Fossati N, Suardi N, Pultrone C, De Groote R, Dovey Z, Umari P, Gallina A, Briganti A, Mottrie A (2017) Robot-assisted salvage lymph node dissection for clinically recurrent prostate cancer. Eur Urol 72(3):432–438CrossRefGoogle Scholar
  50. 50.
    Sweeney C, Nakabayashi M, Regan M, Xie W, Hayes J, Keating N, Li S, Philipson T, Buyse M, Halabi S, Kantoff P, Sartor AO, Soule H, Mahal B (2015) The development of intermediate clinical endpoints in cancer of the prostate (ICECaP). J Natl Cancer Inst 107(12):djv261.  https://doi.org/10.1093/jnci/djv261 Google Scholar
  51. 51.
    Uppal A, Ferguson MK, Posner MC, Hellman S, Khodarev NN, Weichselbaum RR (2014) Towards a molecular basis of oligometastatic disease: potential role of micro-RNAs. Clin Exp Metastasis 31:735–748CrossRefGoogle Scholar
  52. 52.
    Formosa A, Markert EK, Lena AM, Italiano D, Finazzi-Agro’ E, Levine AJ, Bernardini S, Garabadgiu AV, Melino G, Candi E (2014) MicroRNAs, miR-154, miR- 299-5p, miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR- 485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 locus, regulate proliferation, apoptosis, migration and invasion in meta- static prostate cancer cells. Oncogene 33(44):5173–5182CrossRefGoogle Scholar
  53. 53.
    Lussier YA, Xing HR, Salama JK, Khodarev NN, Huang Y, Zhang Q, Khan SA, Yang X, Hasselle MD, Darga TE, Malik R, Fan H, Perakis S, Filippo M, Corbin K, Lee Y, Posner MC, Chmura SJ, Hellman S, Weichselbaum RR (2011) MicroRNA expression characterizes oligometastasis(es). PLoS One 6(12):e28650.  https://doi.org/10.1371/journal.pone.0028650 CrossRefGoogle Scholar
  54. 54.
    Conti A, D’Elia C, Cheng M, Santoni M, Piva F, Brunelli M, Lopez-Beltran A, Giulietti M, Scarpelli MM, Pycha A, Benedetto Galosi A, Artibani W, Cheng L, Montironi R, Battelli N, Lusuardi L (2017) Oligometastases in genitourinary tumors: recent insights and future molecular diagnostic approach. Eur Urol Suppl. 16(12):309–315CrossRefGoogle Scholar
  55. 55.
    Kawakami K, Fujita Y, Kato T, Mizutani K, Kameyama K, Tsumoto H, Miura Y, Deguchi T, Ito M (2015) Integrin β4 and vinculin contained in exosomes are potential markers for progression of prostate cancer associated with taxane-resistance. Int J Oncol 47(1):384–390CrossRefGoogle Scholar
  56. 56.
    Trerotola M, Ganguly KK, Fazli L, Fedele C, Lu H, Dutta A, Liu Q, De Angelis T, Riddell LW, Riobo NA, Gleave ME, Zoubeidi A, Pestell RG, Altieri DC, Languino LR (2015) Trop-2 is up-regulated in invasive prostate cancer and displaces FAK from focal contacts. Oncotarget 6(16):14318–14328 (Erratum in: Oncotarget. 2015;6(32):34038) CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Amine Slaoui
    • 1
    • 2
    • 3
    Email author
  • S. Albisinni
    • 4
  • F. Aoun
    • 2
    • 5
  • G. Assenmacher
    • 2
  • W. Al Hajj Obeid
    • 4
  • R. Diamand
    • 4
  • S. Regragui
    • 1
  • A. Touzani
    • 1
  • A. Bakar
    • 4
  • A. Mesfioui
    • 3
  • T. Karmouni
    • 1
  • A. Ameur
    • 6
  • K. Elkhader
    • 1
  • A. Koutani
    • 1
  • A. Ibnattya
    • 1
  • T. Roumeguere
    • 4
  • A. Peltier
    • 2
  1. 1.Urology B DepartmentIbn Sina Hospital, Mohammed V UniversityRabatMorocco
  2. 2.Urology DepartmentJules Bordet Institute, ULBBrusselsBelgium
  3. 3.Laboratory of Genetics, NeuroEndocrinology and Biotechnology, Faculty of SciencesUniversity Ibn TofailKenitraMorocco
  4. 4.Urology Department, University Clinics of BrusselsErasme Hospital, ULBBrusselsBelgium
  5. 5.Urology DepartmentHôtel Dieu-de-France, Saint-Joseph UniversityBeyrouthLebanon
  6. 6.Urology DepartmentMohammed V Military Hospital, Mohammed V UniversityRabatMorocco

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