Current Guidelines in the treatment of Prostate Cancer: what is most appropriate for Nigerian patients? Dr Emmanuel Ajibola Jeje BSc. M. B. Ch.B; FMCS; FWACS; FICS; FACS Consultant Urologist, Lagos University Teaching Hospital President Nigeria Association of Urological Surgeons

Which Guidelines do you think Prostate Specialists in Nigeria refer to? EAU Guidelines AUA Guideline BAUS Guideline ESMO guidelines NCCN or other US Internal Guidelines from HCPs institution National Guidelines Other guidelines At the Faculty Update meeting held in Nice in May 2011 the delegates (~100- 150) were asked which guidelines do they refer to. They were allowed to select only one option

Which Guidelines do Prostate Specialists in SSA refer to? These are the answers As expected the EAU guidelines were the most popular and this is not surprising given that it was an EMEA audience

Review of Guidelines Compare the following guidelines for similarities and differences on the key issues: EAU ESMO NCCN AUA We have undertook a review of the top 3 guidelines to look for similarities and the differences and then given an overall conclusion for each topic NCCN Guidelines Version 1.2015. Accessed December 2014 ESMO Prostate Cancer :Clinical Practice Guidelines, 2013 EAU Guidelines 2014; Accessed December 2014

Screening EAU ESMO NCCN At present widespread mass screening for PCa is not appropriate Rather, early detection (opportunistic screening) should be offered to the well-informed man No guidance Early detection when applied properly should reduce PCa mortality. However the reduction comes at the expense of over treatment that may occur in as many as 50% of men treated for PSA detected PCa No clear guidance Overall No clear guidance on the use of routine screening of PSA for detection of prostate cancer (PCa) Due to the contradictory evidence on the usefulness of screening, all of the guidelines either do not recommend or do not give any clear guidance on the use of mass screening to detect prostate cancer

General agreement between the guidelines on the diagnosis of PCa EAU ESMO NCCN Serum PSA, DRE & transrectal ultrasnography (TRUS) Need for prostate biopsy made on results from: PSA, DRE, age, co-morbidities. Number of cores: minimum 10 Commonest and the worst Gleason grades should be reported Serum PSA & DRE Need for prostate biopsy made on results from: PSA (3 ng/mL cut off), DRE, age, symptoms, co-morbidities, patient values and family history, TRUS results Number of cores: minimum 8 Biopsy recommended but no guidance given Number of cores: not stated Overall General agreement between the guidelines on the diagnosis of PCa

Staging Stage EAU ESMO NCCN Overall Very Low Not defined T1c Gleason score ≤6 PSA <10 ng/mL Fewer than 3 positive biopsy cores, ≤50% cancer in each core Low Risk T1-T2a Gleason ≤ 6 PSA<10 ng/mL Gleason <7 T1-2a Gleason 2-6 Intermediate T2b-T2c or Gleason score 7 or PSA 10-20 ng/mL All others not fitting into low or high categories High T3a or Gleason score 8-10 or PSA >20 ng/ml T3-4 Gleason >7 PSA >20 ng/mL Very High T3b-T4 N0 or any T, N1 Metastatic M1 Any T, N1 or Any T, Any N, M1 Overall Consistency between definitions for low, intermediate and high but additional stages at the extremes for EAU and NCCN

Treatment Protocol

Consistency between the guidelines on management of low-risk PCa EAU ESMO NCCN Watchful waiting or Active Surveillance Radiotherapy Low dose Brachytherapy Radical prostatectomy Active surveillance external beam radiotherapy, brachytherapy with permanent implants or high-dose rate brachytherapy with temporary implants Radical prostatectomy (RP) Hormone therapy (HT) alone or adjuvant to RP Watchful waiting with delayed HT at symptomatic progression (those unwilling to receive radical treatment) PSA every 6 months (min) DRE every 12 months (min) Repeat biopsy every 12 months Radiotherapy (external beam radiotherapy or brachytherapy) Radical prostatectomy ± pelvic lymph node dissection If adverse features then radiotherapy or observation If lymph node positive then observation or ADT Overall Consistency between the guidelines on management of low-risk PCa

Intermediate Risk EAU ESMO NCCN Overall Watchful waiting or Radiotherapy Radical prostatectomy Brachytherapy Hormonal Combination External beam radiotherapy or brachytherapy with permanent implants If moderate dose of radiotherapy (<60 Gy), ADT for 6 months should be given Watchful waiting with delayed hormone therapy at symptomatic progression (those unwilling to receive radical treatment) Active Surveillance PSA every 6 months (min) DRE every 12 months (min) Repeat biopsy every 12 months Radiotherapy ± short-term ADT (4-6 months) ± brachytherapy Radical prostatectomy ± pelvic lymph node dissection If adverse features then radiotherapy or observation If lymph node positive then observation or ADT Overall Consistency between the guidelines on management of intermediate-risk PCa

Consistency between the guidelines on management of high-risk PCa EAU ESMO NCCN Watchful waiting External Beam Radiotherapy + long-term ADT (3 years) or Radiotherapy + short-term ADT Radical prostatectomy + pelvic lymph node dissection Radical prostatectomy (for N1 disease post-operative ADT) Radiotherapy (external beam) plus (neo)adjuvant treatment (LHRH for 3-6 months) Radiotherapy + long term ADT (≥24 months years or ≥6 months for locally advanced disease, ≥T2b) Watchful waiting with delayed hormone therapy at symptomatic progression (those unwilling to receive radical treatment) Intermittent HT can be offered for locally advanced disease External Beam Radiotherapy ± long-term ADT (2-3 years) (category 1) Radiotherapy + brachytherapy ± long-term ADT (2-3 years) If adverse features then radiotherapy or observation If lymph node positive then observation or ADT± pelvic EBRT Overall Consistency between the guidelines on management of high-risk PCa

? Less acceptance of this category within EMEA Very High Risk EAU ESMO NCCN Watchful waiting or Radical Prostatectomy Radiotherapy + long-term ADT (3 years) Hormonal Combination No guidance External Beam Radiotherapy ± long-term ADT (2-3 years) (category 1) Radiotherapy + brachytherapy ± long-term ADT (2-3 years) Radical prostatectomy + pelvic lymph node dissection If adverse features then radiotherapy or observation If lymph node positive then observation or ADT ± pelvic EBRT ADT in selected patients Overall NCCN guidelines have more detail guidance on management of very-high risk PCa. ? Less acceptance of this category within EMEA

M0 or M1 ADT-Naïve Patients EAU ESMO NCCN Watchful waiting or Radical prostatectomy Radiotherapy Hormonal Orchiectomy Lifelong ADT LHRH agonist alone ± anti-androgen to prevent testosterone flare Any T, N1 ADT EBRT +ADT (2-3 y) (category 1) Or Any T,N,M1 Overall Guidelines provide similar recommendations for management of M0 and M1 PCA

Asymptomatic mCRPC Chemotherapy-Naïve Patients EAU ESMO NCCN Performans Status 0 or 1 with no visceral metastasis Abiraterone Enzalutamide Sipuleucel T or Second-line hormone therapy (antiandrogen, antiandrogen withdrawal, estrogen, steroids) Performans Status 2+ Monitoring Anti- androgens Second-line hormone therapy (antiandrogen, antiandrogen withdrawal, estrogen, ketoconazole, steroids) Sipuleucel-T Clinical trial Docetaxel (should be discussed with asymptomatic patients) No Visceral Metastases Enzalutamide (category 1) Abiraterone acetateX with prednisone (category 1) Docetaxel + prednisone (category 1) Radium-223 for symptomatic bone metastases (category 1) Secondary hormone therapy Antiandrogen Antiandrogen withdrawal Ketoconazole Corticosteroids Clinical trials X For patients who are not candidates for docetaxel-based regimens Overall In NCCN Guidelines Replaced «syptomatic» with «visceral disease». Abiraterone and enzalutamide are recommended by EAU and NCCN Guidelines.

Symptomatic mCRPC EAU ESMO NCCN Overall Androgen suppression should therefore be continued indefinitely in these patients First line options include PS 0-1 no visceral mets: Docetaxel Alpharadin (Radium-223) First line options include PS 0-1 visceral mets: Performans Status 2+ Docetaxel using a 3-weekly schedule should be considered for Symptomatic CRPC Second-line options include: Abiraterone (post-docetaxel) Cabazitaxel (post docetaxel) Docetaxel rechallenge Mitoxantrone Enzalutamide (if available) Radium-223 (if available) Visceral Metastases Docetaxel + prednisone (category 1) Enzalutamide (categoty 1) Abiraterone acetatex with prednisone Alternative chemox (mitoxantrone) Clinical trial X For patients who are not candidates for docetaxel-based regimens Overall Docetaxel is the preferred chemotherapy. 2nd line options post-docetaxel are cabazitaxel and abiraterone, enzalutamide

Subsequent therapy for mCRPC with no visceral metastases EAU ESMO NCCN Second line options include: (dependent on previous treatment) Docetaxel Abiraterone Enzalutamide Cabazitaxel Radium-223 no visceral mets. NA Prior therapy enzalutamide/abiraterone: Docetaxel + prednisone (category 1) Abiraterone acetate or enzalutamide Radium-223 (category 1) If bone-predominant disease Sipuleucel-T If asymptomatic or minimally symptmatic,no liver metastases,life expectancy >6 mo,ECOG 0-1 Clinical trial Other secondary hormone therapy Antiandrogen Antiandrogen withdrawal Ketoconazole Corticosteroids DES or other Estrogen Best supportive care Prior therapy Docetaxel: Enzalutamide (categoty 1) Abiraterone acetate with prednisone(categoty 1) Cabazitaxel with prednisone (category 1) Alternative chemo (mitoxantrone) Docetaxel rechallenge Other secondary hormone therapy and Best supportive care(see above) Overall 2nd line options post-docetaxel are cabazitaxel and abiraterone, enzalutamide, 2nd line options post- abi/enza are docetaxel,radium 223,abiraterone or enzalutamide,sipuleucel-T

Subsequent therapy for mCRPC with visceral metastases EAU ESMO NCCN Second line options include: (dependent on previous treatment) Docetaxel Abiraterone Enzalutamide Cabazitaxel Radium-223 no visceral mets. NA Prior therapy enzalutamide/abiraterone: Docetaxel + prednisone (category 1) Clinical Trial Abiraterone acetate or enzalutamide Other secondary hormone therapy Antiandrogen Antiandrogen withdrawal Ketoconazole Corticosteroids DES or other Estrogen Best supportive care Prior therapy Docetaxel: Enzalutamide (categoty 1) Abiraterone acetate with prednisone(categoty 1) Radium-223 (category 1) If bone-predominant disease Cabazitaxel with prednisone (category 1) Docetaxel rechallenge Alternative chemo (mitoxantrone) Clinical trial Other secondary hormone therapy and Best supportive care (see above) Overall 2nd line options post-docetaxel are cabazitaxel and abiraterone, enzalutamide, 2nd line options post- abiraterone/enzalutamide are docetaxel,abiraterone or enzalutamide

Use of Bisphophonates EAU ESMO NCCN Overall The optimal regimen for zoledronic acid is unclear One study recommends treatment every 3 weeks, while another trial has produced similar results with an annual injection The initial BMD could be used to guide the choice of regimen Denosumab may prevent further SREs Benefit vs risk must be carefully weighed Denosumab or zoledronic acid to delay SREs In CRPC patients with bone metastases, denosumab and zoledronic acid have been shown to prevent disease-related skeletal complications Optimal duration of therapy of either drug remains uncertain Overall Bisphosphonates are recommended only for patients with bone metastases. Both zoledronic acid and denosumab are equally recommended

Which of these Guidelines do you think is best suited for our patients in Nigeria? EAU Guidelines AUA Guideline BAUS Guideline ESMO guidelines NCCN or other US Internal Guidelines from HCPs institution National Guidelines Other guidelines At the Faculty Update meeting held in Nice in May 2011 the delegates (~100- 150) were asked which guidelines do they refer to. They were allowed to select only one option

Conclusion General consistency between the guidelines on prostate cancer EAU are the most comprehensive of the European guidelines NCCN guidelines provide most in-depth and up to date information on the management of prostate cancer Novel agents (abiraterone, cabazitaxel, enzalutamide, radium-223) are now being included in the guidelines Urgent need for National guideline

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