Committee I

Committee VI

Prostate Cancer

Prof. Amr Nowier, MD, Professor of Urology, Ain Shams University

Prof. Mohamed Abdella, MD, Professor of Oncology, Cairo University

Prof. Ahmed Tawfik, MD, Professor of Urology, Ain Shams University

Dr. Mai Ezz Eldin, MD, Lecturer of Oncology, Ain Shams University

Dr. Mohamed Shabayek, MD, Lecturer of Urology, Ain Shams University

Dr. Mohamed Hefny, MD, Lecturer of Oncology, Ain Shams University

Contents
VI.1 List of Abbreviations
  • AS - Active surveillance
  • ADT - Androgen deprivation Therapy
  • ARTA - Androgen Receptor Targeting Agents
  • CRPC - Castration-resistant Prostate Cancer
  • dMMR - Defective Mismatch Repair
  • DRE - Digital Rectal Examination
  • ePLND - Extended Pelvic Lymph Node Dissection
  • eLND - Extended Pelvic Lymph Node Dissection
  • EBRT - External-Beam Radiation Therapy
  • HRQoL - Health Related Quality of Life
  • HIFU - High Intensity Focused Ultrasound
  • HDR - High-Dose Rate
  • HRD - Homologous Recombination Deficiency
  • HFX - Hypofractionation
  • IMRT - Intensity Modulated Radiotherapy
  • IPSS - International Prostatic Symptom Score
  • LAPC - Locally advanced prostate cancer
  • LDR - Low-Dose Rate
  • LN - Lymph Node
  • LND - Lymph Node Dissection
  • MRI - Magnetic Resonance Imaging
  • MFS - Metastasis Free Survival
  • PCa - Metastatic Castration-Resistant
  • mHSPC - Metastatic Hormone Sensitive Prostate Cancer
  • MSI - Microsatellite Instability
  • mpMRI - Multiparametric Magnetic Resonance Imaging
  • NEPC - Neuroendocrine Prostate Cancer
  • NGI - Next-Generation Imaging
  • OMPC - Oligometastatic Disease
  • PLND - Pelvic Lymph Node Dissection
  • PARP - PolyADP-Ribose Polymerase
  • PET - Positron Emission Tomograpgy
  • PCa - Prostate Cancer
  • PSA - Prostate-Specific Antigen
  • RP - Radical Prostatectomy
  • RT - Radiotherapy
  • SRE - Skeletal-Related Events
  • TURP - Transurethral Resection Of The Prostate
  • VMAT - Volumetric Arc External-Beam Radiotherapy
  • WW - Watchful Waiting

VI.2 Abstract

VI.2.1 Objectives.
The Urologic Egyptian Guidelines on prostate cancer aim to help and guide clinical practitioners to have knowledge of the incidence, standard definitions, diagnosis, therapy, and follow-up of prostate cancer patients

VI.2.2 Methods
Databases searched included Medline, Cochrane Libraries, EAU guidelines, AUA and NICE guidelines, from January 2018 and September 2020.

Review of several meta-analyses, leading institutional protocols and relevant Egyptian publications were taken into consideration. All statements were graded according to Strength Rating of recommendation. Each statement was given a Strength Rating rating (strong or weak).

VI.2.3 Results
These guidelines represent the best clinical evidence-based medicine available. These guidelines are not solely based upon the level of evidence of the international publications but also include expertise of the treating doctor and expectations of every patient.

VI.2.4 Conclusions.
These guidelines provide practical evidence-based guidance on the clinical aspect of prostate cancer. The main target is entirely focused on assessment and treatment, reflecting the recommended clinical practice. This can provide the basis for thinking through patient’s management and also for planning and designing clinical services.

Prostate cancer is a complex disease, in which disease characteristics, age, comorbidities and individual patient preference will impact treatment choice. All available management options need to be discussed, in full, with the patient.

VI.3 Introduction
Prostate cancer is the most frequent male cancer above the age of 50 years. In Egypt, it´s the 6th most common male cancer according to the National population based Registry program of Egypt 2008-2011, but the exact prevalence depends on the frequent use of PSA and DRE for males above age of 50 years. Prostate cancer is very heterogenous and complexed disease that necessitates individualized treatment including patient´s preferences through MDT.

This Guideline covers the diagnosis and management of prostate cancer based on revision of many Guidelines like EAU, NICE and NCCN guidelines that use the best evidence and recommendation.

Professional and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients. It is not mandatory to apply the recommendations, and this guideline does not override the responsibility to make decisions appropriate to the circumstances´ of the individual, in consultation with them and their families.

This guideline also takes in consideration values and believes of Egyptian patients and the economic status of Egypt as a low resource country.

VI.4 Screening and early detection of prostate cancer
Pca is a common disease, it grows so slowly and rarely causes symptoms, so most men die of other causes before the disease becomes clinically or impact the survival. At the same time, Increased detection of prostate cancer subjects some patients to the risks associated with treatments that may not prolong life and have risks of morbidity. So, screening for early detection of PCa is one of the most controversial topics in the urological literature

VI.4.1 Benefits and harms prostate cancer screening
  • Cochrane review and others reported that screening increases the detection of prostate cancer and reduces the rates of advanced disease at the time of diagnosis. (1,2,3)
  • Effect of screening on mortality “the most controversial topic”, Some noted a greater decline in prostate cancer mortality rate, (4,5,6). Others reported there was no difference in prostate cancer mortality between the screened and non-screened in the (PLCO) trial. (7) Also Schröder FH from (ERSPC) trial reported that with extended follow up, the mortality reduction remains unchanged. (8) at the same time a Cochrane review reported that screening have no benefit on PCa-specific survival and overall survival. (3)
  • There is over diagnosis and treatment. Schröder et al, 2014 reported that to prevent one Pca death we would need to screen 781 men and diagnose an additional 27 men at a median follow-up of 13 years. (8) the same result obtained from (PLCO) trial.
  • False-result of PSA. It may be abnormal even if there is no Pca such patients may have anxiety about their test result and/or may at risks related to prostate biopsy, and it may be normal even if there is Pca.
  • Risk of prostate biopsy
  • Risk of treatment

VI.4.2 Screening for early detection
The American College of Preventive Medicine recommends against routine population screening (9). Shared decision-making (Patients and clinicians should engage in shared decision)

Points that must be discussed in shared decision-making
  • Benefits and harms of screening
  • Use nomograms to help with decision making, predict biopsy results, predict pathological stage and predict risk of treatment failure
  • Screening is done with a PSA test which is repeated every1-2 years.
  • Additional tests may be done to assess elevated PSA. No available tests can accurately determine which men have a cancer that may cause health problems.
  • Prostate biopsy may be needed any may be repeated
  • Discuss all treatment options and their risks and benefits in an objective, unbiased manner

Table VI:1 Recommendations for screening for early detection

Recommendation

Strength Rating
1. Screening should be in shared decision-making Strong
2. Systematic population-based screening for Prostate cancer Weak
VI.4.3 Approach for Screening
PSA testing alone or in combination with Digital rectal examination. (10)
  • If DRE was performed, PSA can be measured immediately as DRE leads to minimal transient PSA elevations of 0.26 to 0.4 ng/mL
  • Patient who is repeating PSA test to evaluate a result that was close to a cutoff should abstain for at least 48 hours from activities that induce perineal trauma (eg, ejaculation or bicycling).

Table VI:2 Reasons to temporarily defer PSA testing

Causes

Time to defer
Bacterial prostatitis 6-8 weeks after symptoms resolve
Urethral instrumentation 2 weeks
Prostate biopsy or (TURP) 6 weeks
PSA derivatives:

PSA derivatives are used to increase the specificity of PSA testing and improve detection of Pca. They are of no benefit in men with PSA >10 ng/mL or less than 4 ng/ml. They include: PSA density, PSA density of the transition zone, PSA velocity, age-specific PSA, f/t ratio, free PSA isoforms and complexed PSA forms

Table VI:3 Recommendations for PSA derivatives

Recommendation

Strength Rating
1. PSA in combination with DRE is the most appropriate test for screening. Strong
2. Men with abnormal DRE should be referred to biopsy, regardless PSA result. Strong
3. A man taking a 5-ARI the PSA should corrected before interpretation. Strong
VI.4.4 Age to begin discussing screening
  • At age 50 or 55 years to 69 years for average-risk men as long as life expectancy is at least 10- 15 years
  • At age 40 or 45 years old for higher-risk men
  • BRCA1 or BRCA2 genetic mutations, black men, men with a family history of prostate cancer, particularly in a first-degree relative who was diagnosed at age <65 years and men with a PSA > 1 ng/mL at 40 years or > 2 ng/mL at 60 years

Table VI:4 Recommendations for Age to Begin Discussing Screening

Recommendation

Strength Rating
1. Men screened for Pca should have a life expectancy of at least 10 -15 years Strong
2. Race, age, and family history are used to identify risk for prostate cancer Strong
3. In average-risk men, initiate discussion of screening is at age 50 or 55 years Strong
4. Men at higher risk, initiate discussion of screening is at age 40 or 45 years Strong
VI.4.4.1 Frequency of screening
No specific screening interval. Expert guidelines vary as to screening interval recommendations.

Some recommend repeating PSA testing every two years whereas others repeat PSA annually. Based on the ERSPC, screening intervals of two years preserve the majority of the benefits and reduce over-diagnosis and false positives.

Other recommend to adjust the frequency of testing based on the prior PSA result, with less frequent retesting in men with lower initial PSA levels and annual testing in those with higher PSA levels that are still below a cutoff for biopsy. (11, 12)

VI.4.4.2 Discontinuing screening
  • Patients have a life expectancy of <10 to15 years.
  • Most clinicians offer screening up to age 70 years

Table VI:5 Recommendations for Discontinuining Screening

Recommendation

Strength Rating
1. Screening interval of one to two years Strong
2. Screening up to age 70 years, stopping earlier if comorbidities limit life expectancy to less than 10 years Strong
VI.4.5 Prostatic biopsy
VI.4.5.1 Baseline biopsy
  • (US)-guided is the standard of care. It is performed by trans-rectal or trans-perineal approach. Cancer detection rates, when performed without prior (MRI), are comparable between the two approaches. (13)
  • TURP should not be used as a tool for biopsy. (14)
  • The decision for biopsy is based on elevated PSA and/or suspicious DRE and/or imaging. Recently, prostate cancer risk calculators have been developed to estimate the risk of prostate cancer from multiple parameter, thereby reducing the number of unnecessary biopsies. Common calculator used are: the PCPT cohort: PCPTRC 2.0 the ERSPC cohort: http://myprostatecancerrisk.com/, the ERSPC cohort: http://www.prostatecancer-riskcalculator.com/seven-prostate-cancer-risk-calculators and a local Canadian cohort: https://sunnybrook.ca/content/?page=asure=calc

VI.4.6 Elevated PSA
  • It should not prompt immediate biopsy. It should be verified after a few weeks, in the same laboratory, using the same assay under standardized conditions (i.e. no ejaculation, manipulations, and [UTIs]). (15,16)
  • Empirical use of antibiotics in an asymptomatic patient to lower the PSA not recommended. (17)
  • PSA depravities and new biological markers such as TMPRSS2-ERG fusion, PCA3 or kallikreins as Phi or 4Kscore tests increase sensitivity and specificity of PSA, so avoiding unnecessary biopsies. (18-21)
  • For people who have a raised PSA and MRI Likert score of 1 or 2, omit biopsy based on shared decision making with the patient, repeat PSA test at 3 to 6 months and:
    • If there is a strong suspicion of prostate cancer (for example, PSA density greater than 0.15 ng/ml/ml or PSA velocity greater than 0.75 ng/year, or strong family history), offer prostate biopsy considering their life expectancy and comorbidity
    • If the level of suspicion is low; advise PSA to follow up at 6 months and then every year, and set a PSA level to biopsy based on PSA density (0.15 ng/ml/ml) or velocity (0.75 ng/year).

VI.4.7 Abnormal DRE
An abnormal DRE is associated with an increased risk of a higher ISUP grade and is an indication for biopsy. (22,23)

VI.4.8 Imaging
  • Grey-scale TRUS and ultrasound-based techniques is not reliable at detecting PCa. (24)
  • Multiparametric magnetic resonance imaging (mpMRI)
  • Because of its low specificity, mpMRI in very low-risk patients would result in an inflation of false-positive findings and subsequent unnecessary biopsies.so mpMRI must not be used in patients who do not have an indication for prostate biopsy based on their family history and clinical and biochemical data.
  • Cochrane meta-analysis and others reported that (mpMRI) has good sensitivity for the detection and localization of ISUP grade ≥2 cancers. (25-28), also it reported that (mpMRI) is poor sensitive in identifying ISUP grade 1 PCa. (25)
  • MRI-TBx improve the detection of ISUP grade ≥2 as compared to systematic biopsy especially in patients with prior negative systematic biopsy, but not in biopsy-naïve men. In biopsy-naïve patients, the difference is to be less marked; it is not significant in all series, but remains in favor of MRI-TBx in some studies. (25, 29-33)
  • MRI-TBx reduce the detection of ISUP grade 1 PCa as compared to systematic biopsy. So, MRI-TBx significantly reduces over-diagnosis of low-risk disease, as compared to systematic biopsy. (25,31-33)
  • Combined target and systemic biopsy of the lobe with the MRI lesion increase the detection of csPCa (ISUP grade ≥2) in compare with target biopsy alone from 73.5% to 96%. (34)
  • csPCa can be missed because of MRI failure (invisible cancer or reader’s misinterpretation) or because of targeting failure (target missed or undersampled by MRI-TBx).
  • Limitations of the ‘MR pathway’ are the moderate inter-reader reproducibility of mpMRI and the lack of standardisation of MRI-TBx (minimum number of targeted cores to be obtained as a function of the prostate volume, lesion size and location), as well as the fact that its inter-operator reproducibility has not been evaluated.

Sampling sites and number of cores

  • Where no prior imaging with mpMRI, or where mpMRI has not shown any suspicious lesion, the sample sites should be bilateral from apex to base, as far posterior and lateral as possible in the peripheral gland.
  • Additional cores should be obtained from suspect areas.
  • At least eight systematic biopsies are recommended in prostates with a size of about 30 cc. Sextant biopsy is no longer recommended.
  • Ten to twelve core biopsies are recommended in larger prostates
  • Saturation biopsy (> 20 cores):
    • It may be performed with the trans-perineal technique, which detects an additional 38% of PCa. The rate of urinary retention is high (10%)
    • Seminal vesicle biopsy:
    • Not recommended due to low its value.
    • Its added value compared with mpMRI is questionable.
  • Transition zone biopsy during baseline biopsies has a low detection rate and should be limited to repeat biopsies

VI.4.9 Repeat biopsy after previously negative biopsy
  • The PCA3 assay and PHI is not recommended in people having investigations for suspected prostate cancer who have had a negative prostate biopsy
  • The decision for repeat the biopsy has to be considered when there is high probability of Pca despite negative initial biopsy as in: rising and/or persistently elevated PSA, suspicious DRE, 5-30% PCa risk (35,36), positive (mpMRI) Likert score of 3 or more, ASAP, 31-40% PCa risk on repeat biopsy, (37,38) extensive (> 3 site) (HGPIN), ~30% PCa risk (38,39), a few atypical glands adjacent to (HGPIN), ~50% PCa risk. (40), intraductal carcinoma, > 90% risk of associated high-grade PCa. (41)
  • For people who have a raised PSA, an MRI Likert score of 1 or 2, and negative biopsy, repeat PSA at 3 to 6 months and:
    • If there is a strong suspicion of prostate cancer (for example, PSA density greater than 0.15 ng/ml/ml or PSA velocity greater than 0.75 ng/year, or strong family history), offer prostate biopsy considering their life expectancy and comorbidities
    • If the level of suspicion is low; advise PSA follow‑up every 2 years, and set a PSA level for re-biopsy based on PSA density (0.15 ng/ml/ml) or velocity (0.75 ng/year).

Table VI:6 Recommendations for Prostate Biopsy

Recommendation

Strength Rating
1. The initial biopsy is based on PSA and DRE. Do not automatically offer a prostate biopsy on the basis of serum PSA level alone Strong
2. In asymptomatic men with normal DRE and elevated PSA between 4-10 ng /dl to avoid unnecessary biopsies, offer further risk-assessment by use one of the followingtools.
  • Pcarisk-calculator
  • Image (multiparametric MRI)
  • An additional serum or urine-based test.
 Strong
3. Do not offer transition zone or seminal vesicle sampling at initial biopsies due to low detection rates Strong
4. Do not use transurethral resection of the prostate as a tool for cancer detection Strong
5. people decide whether to have an MRI or prostate biopsy by discussing: PSA level, DRE findings, any comorbidities, risk factors (including increasing age and black African-Caribbean family origin) and any history of a previous negative prostate biops Strong
6. Do not use mpMRI as an initial screening tool. Strong
7. Do not routinely offer mpMRI to people with prostate cancer who are not going to be able to have radical treatment Strong
8. Adhere to PI-RADS guidelines for mpMRI acquisition and interpretation. Strong
Table VI:7 Recommendations for Biopsy Naïve Patients

Recommendation

Strength Rating
1. Offer mpMRI as the first-line investigation before prostate biopsy for people with suspected clinically localized Pca. Recommended
2. When mpMRI is positive (i.e. PI-RADS ≥3), combine targeted and systematic biopsy. Strong
3. When mpMRI is negative (i.e. PI-RADS ≤2), and clinical suspicion of prostate cancer is low, omit biopsy based on shared decision making with the patient and repeat PSA test at 3 to 6 months. If person opts to have a biopsy, offer systematic prostate biopsy. Recommended
Table VI:8 Recommendations for patients with prior negative biopsy

Recommendation

Strength Rating
1. Perform mpMRI before prostate biopsy. Strong
2. When mpMRI is positive (i.e. PI-RADS > 3) repeat, the biopsy is mandatory but target biopsy only. Strong
3. When mpMRI is negative (i.e. PI-RADS < 2), and clinical suspicion of prostate cancer is high, perform systematic biopsy based on shared decision Strong
VI.5 Locally Confined Disease
Risk stratification is essential for appropriate management of patients with prostate cancer after initial diagnosis. Combination of DRE for clinical staging, serum total PSA, local and nodal staging through cross sectional imaging CT or mpMRI and metastatic work up evaluation as well as TRUS guided biopsy parameters (Gleason score, number of positive cores, percentage of core infiltration) are needed for assessment of prostate cancer risk and planning further management.

VI.5.1 5.1 Risk Stratification of Locally Confined Prostate Cancer
Table VI:9 Definition of Different Risk Groups

Very Low-risk

Low-risk

Intermediate- risk

High-risk
PSA <10ng/ml and GS<7 (ISUP grade 1) and cT1-2a and <34% of Bx cores +ve and no core >50% +ve and PSA density <0.15 ng/ml/cc PSA < 10 ng/mL and GS<7 (ISUP grade 1) and cT1-2a PSA 10-20 ng/mL or GS7 (ISUP grade 2/3) or cT2b PSA > 20 ng/mL or GS>7 (ISUP grade 4/5) or cT2c any PSA any GS (any ISUP grade) cT3-4 or cN+
Localized Locally advanced
GS = Gleason score; ISUP = International Society for Urological Pathology; PSA = prostate-specific antigen.
Patients with prostate cancer should be managed after counseling with multidisciplinary team including urologists, medical and radiation oncologists, pathologists and radiologists. Patients should be informed on the effect of each treatment modality on the survival, oncologic control as well as treatment related adverse effects.

Table VI:10 Recommendations for Risk stratification of locally confined prostate cancer

Recommendation

Strength Rating
1. Risk stratification is essential for planning further management of patients diagnosed with prostate cancer Strong
2. Bone scans should not be offered to asymptomatic very low or low-risk localized prostate cancer. Strong
3. Discuss with prostate cancer patients all appropriate treatment modalities based on the risk stratification of prostate cancer Strong
4. Management of prostate cancer should be after multidisciplinary team including urologist, medical and radiation oncologists, pathologists and radiologists Strong
5. Counsel patients with prostate cancer on survival benefit, risk of progression and treatment related adverse effects of each treatment modality based on risk stratification Strong
VI.6 General guidelines for management of PCa
VI.6.1 Deferred treatment
Watchful waiting is a conservative palliative management for patients with life expectancy < 10 years unfit or refusing active treatment, where patients are not offered any active treatment till the development of local or systemic progression or become symptomatic.

Active surveillance is a form of deferred treatment aiming at avoiding unnecessary treatment in patients with clinically localized disease with low risk for progression to avoid treatment related adverse effects with active intervention in presence of signs of disease progression.

Table VI:11 Difference between two forms of deferred treatment of prostate cancer

Active surveillance (42)

Watchful waiting
Target patients Low risk and some intermediate risk patients with life expectancy >10 years All risk patients with life expectancy <10 years
Aim Curative treatment with predefined follow up schedule to minimize treatment related side effects without compromising survival Palliative treatment to selected patients with all risk stages to minimize side effects for patient not fit for active treatment
Watchful waiting should not be offered to asymptomatic patients with prostate cancer with life expectancy > 10 years or patients with high risk disease. (43)

Table VI:12 Recommendations for Asymptomatic Patients with Prostate Cancer

Recommendation

Strength Rating
1. Offer watchful waiting for selected asymptomatic patients with life expectancy <10 years if not accepting treatment related side effects after counseling on the patient for risk of progression Weak
2. Active treatment should be recommended for patients with life expectancy > 10 years based on risk stratification and counseling of patients Strong
VI.6.2 Active treatment
Active treatment for prostate cancer include radical prostatectomy (RP), radiotherapy (RT), androgen deprivation therapy (ADT) and other minimally invasive techniques e.g High intensity focused ultrasound (HIFU), cryotherapy and focal therapy.

Active treatment should be offered to prostate cancer patients after appropriate counseling in absence of contraindication for this form of active treatment and accepting treatment related adverse effects.

Table VI:13 Recommendations for Active Treatment

Recommendation

Strength Rating
1. Inform patients that no active treatment modality has shown superiority over any other active or deferred treatment in terms of survival in low risk disease Strong
2. Counsel patients on side effects of all active treatments and discuss with the patients’ pros and cons of each treatment modality. Strong
3. Discuss the effect of active treatment of prostate cancer on potency, fertility, urinary continence and bowel function. Strong
VI.6.2.1 Surgical treatment: radical prostatectomy
Radical prostatectomy (RP) should be offered for localized prostate cancer patients and selected patients with locally advanced disease based on risk stratification with or without extended pelvic lymph node dissection.

RP can achieve adequate cancer control in localized prostate cancer patients, however may jeopardize postoperative urinary continence, sexual function and health related quality of life (HRQoL). (44)

Different surgical approaches may be adopted during RP including open, laparoscopic and robotic techniques with equal oncologic and functional outcomes. (45)

Extended pelvic lymph node dissection should be done if risk of lymph node involvement is > 5% and there is no value for limited lymphadenectomy in the setting of radical prostatectomy. (46,47)

Nerve sparing radical prostatectomy and meticulous dissection at the apex of the prostate may improve postoperative functional outcomes; better sexual and urinary functions. If Nerve sparing RP is planned, a preoperative mpMRI should be done for detection of extracapsular extension and appropriate counseling of the patient. (48, 49)

Table VI:14 Recommendations for Surgical Treatment (Radical Prostatectomy)

Recommendation

Strength Rating
1. Inform patients that no surgical approach for radical prostatectomy (open, laparoscopic- or robotic) has clearly shown superiority in terms of functional or oncological results. Strong
2. Inform the patient that in experienced hands laparoscopic and robotic surgery has less perioperative morbidity Strong
3. Perform an extended pelvic lymph node dissection (ePLND), when a LND is deemed necessary. Strong
4. Do not perform pelvic lymphadenectomy with radical prostatectomy in very low and low risk prostate cancer Strong
5. Do not offer nerve sparing surgery when there is a risk of extracapsular extension (based on imaging CT/mpMRI, ISUP grade, nomogram). Strong
6. Preoperative mpMRI should be performed if neve sparing radical prostatectomy is planned Strong
VI.7 Radiotherapy (RT)
VI.7.1.1.1 External beam radiotherapy

Intensity-modulated radiotherapy (IMRT) and volumetric arc external-beam radiotherapy (VMAT) are the gold standard for EBRT using multi-leaf collimators so that each radiation beam can be continuously controlled providing adequate and precise radiation doses to particular parts of the radiation field optimizing radiation dose with reduction of treatment related side effects to neighbor tissues especially the rectum to avoid bowel related symptoms after EBRT. (50,51)

IMRT with of image guided radiotherapy can help to monitor organ movement allowing dose escalation with increased toxicity to normal surrounding tissues. (52)

The concept of hypofractionation (HFX) relies on delivering fewer fractions of higher single doses of radiotherapy ≥2.5 Gy per fraction increases treatment efficacy (53), shortens treatment time and reduce treatment cost without increasing early or late adverse effects. (54)

VI.7.1.1.2 Brachytherapy

There are two methods to deliver brachytherapy; Low-dose rate brachytherapy and High-dose rate (HDR) brachytherapy.

Low dose rate brachytherapy may be offered to selected low and intermediate risk patients; stage cT1b-T2a N0, M0; ISUP grade 1 with < 50% of biopsy cores involved with cancer or ISUP grade 2 with < 33% of biopsy cores involved with cancer; an initial PSA level of < 10 ng/mL; a prostate volume of < 50 cm3; an IPSS < 12 and maximal flow rate > 15 mL/min. (55).

High dose radiation can be delivered in single or multiple fractions and is usually used in combination with EBRT of > 45 Gy in patients with intermediate and high risk prostate cancer. (56)

Table VI:15 Recommendations for Radiotherapy (RT)

Recommendation

Strength Rating
1. Offer intensity-modulated radiation therapy (IMRT) or volumetric arc external-beam radiotherapy (VMAT) for definitive treatment of PCa by external-beam radiation therapy. Strong
2. Offer moderate hypofractionation (HFX) with IMRT/VMAT, including image-guided radiation therapy to the prostate, to carefully selected patients with localized disease. Strong
3. Ensure that moderate HFX adheres to radiotherapy protocols from trials with equivalent outcome and toxicity, i.e. 60 Gy/20 fractions in four weeks or 70 Gy/28 fractions in six weeks. Strong
4. Inform patients undergoing external beam radiotherapy of increased risk of colorectal cancer Strong
5. Offer Low dose brachy therapy to selected patients with low or intermediate risk prostate cancer if not contraindicated Weak
6. Offer High dose brachytherapy in combination with EBRT in intermediate and high risk prostate cancer Strong
7. Offer radiotherapy in conjunction with ADT in intermediate and high risk prostate cancer Strong
VI.7.1.1.3 Investigational therapies

Various techniques for either whole gland ablation and/or focal therapy e.g high-intensity focused US (HIFU), cryotherapy and focal photodynamic therapy.

HIFU employs focused ultrasonic waves produced by a transducer to heat malignat tissues above 65°C to cause coagulative necrosis by cavitation (57). It can be performed under general or regional spinal anesthesia.

Cryotherapy depends on tissue freezing to induce dehydration of cells and protein denaturation, through direct destruction of cellular membranes by ice crystals and microthrombi resulting in ischaemic apoptosis (58,59)

Focal therapy to ablate malignant foci is a new alternative for standard treatment to minimize adverse effects of whole gland ablation. It can be applied through various techniques e.g, HIFU, cryotherapy, photodynamic therapy, or brachytherapy. (60,61)

Table VI:16 Recommendations for focal therapy

Recommendation

Strength Rating
1. Cryotherapy and high-intensity focused ultrasound should only be offered within a clinical trial setting. Strong
2. Only offer focal therapy within a clinical trial setting. Strong
VI.8 Management of prostate cancer according to risk group stratification
VI.8.1 Guidelines for first-line treatment of Very Low and Low risk disease
Patients with very low and low risk prostate cancer can choose either active surveillance or active treatment (radical prostatectomy or radiotherapy) after comprehensive counseling on the benefit and harms of each modality as well as survival benefit and disease progression.

No survival benefit for active treatment over active surveillance in this risk group, however active treatment reduce risk for disease progression and development of distant metastases compared to active surveillance. (62)

Active surveillance may maintain better urinary and sexual functions compared to radical prostatectomy and radiotherapy. Radical prostatectomy may jeopardize early postoperative urinary and sexual function with subsequent improvement over time. Radiotherapy has more adverse effect on bowel function compared to AS and RP.

Multiparametric MRI to people having active surveillance who have not had an MRI previously. If the MRI results do not agree with the biopsy findings, offer a new MRI-influenced biopsy. (62)

Selection criteria for AS:

Selection criteria are mostly driven from the DETECTIVE Study (63)

The criteria include: ISUP grade 1, a clinical T1c or T2a, a PSA < 10 ng/mL and a PSA density < 0.15 ng/mL/cc (64,65)

Patients with prostate cancer on AS should be informed that active treatment may be necessary on evidence of disease progression (evidence of metastases or diagnosis of clinical T3 or T4 disease or need for long-term androgen deprivation therapy or rectal fistula or the need for a urinary catheter owing to local tumor growth). (62)

Disease progression may be suspected if there was:
  • Any rise in prostate-specific antigen (PSA) >20% between consecutive measures at any time during follow-up or
  • Any rise in PSA level of 50% or greater in any 12-month period confirmed by repeat tests or
  • Any indication of the appearance of symptomatic systemic disease. (62)

Table VI:17 Recommended schedule for AS

First year (62)

Second year and thereafter
PSA PSA every 3-4 months
Monitor PSA kinetics (PSA velocity and density)		 PSA every 6 months
Monitor PSA kinetics (PSA velocity and density)
DRE Every 12 months
mpMRI At 12-18 months then mpMRI and/or re-biopsy if clinical progression or PSA changes at any time.
Table VI:18 Recommendations of watchful waiting and active surviellance

Recommendation

Strength Rating
1. Low Risk Prostate Cancer is to be diagnosed after at least 12 core prostate biopsies including TZ Strong
Watchful waiting (WW) 2. Offer a WW policy to asymptomatic patients with a life expectancy < 10 years (based on comorbidities). Weak
3. Patients with localized prostate cancer on watchful waiting having evidence of significant disease progression (rapidly rising PSA level or bone aches) should be re-evaluated and counseled on further management Strong
Active surveillance (AS) 1. Offer AS Only to patients with very low risk PCa Strong
2. Offer (Discuss) AS to patients suitable for curative treatment but with low-risk PCa. Strong
3. Refrain from/Stop AS to patients having non-compliance issues Strong
4. Perform multiparametric magnetic resonance imaging (mpMRI) before a confirmatory biopsy, if not done before the first biopsy. Strong
5. Perform the combination of targeted biopsy (of any PI-RADS ≥ 3 lesion) and systematic biopsy at confirmatory biopsy. Weak
6. Base follow up on digital rectal examination, prostate-specific antigen (PSA) and repeated biopsies. Strong
7. Counsel (Inform) patients about the possibility of needing further treatment in the future. Strong
8. Offer radical treatment to people with localized prostate cancer who had chosen active surveillance and develop evidence of disease progression. Strong
Patients with very low and low-risk prostate cancer should be counseled on various forms of active treatment; radical prostatectomy versus radical radiotherapy or other minimally invasive treatments for selected patients if not contraindicated.

Table VI:19 Recommendations for Patients with Very Low and Low Risk Prostate Cancer

Treatment

Recommendation

Strength Rating
Active treatment Offer surgery and radiotherapy (RT) as alternatives to AS to patients suitable for such treatments and who accept a trade-off between toxicity and prevention of disease progression. Weak
Pelvic lymph node dissection (PLND) Do not perform a PLND (estimated risk for pN+ < 5%). (very low and low risk PCa if Chose RP) Strong
Radiotherapy Offer low-dose rate (LDR) brachytherapy to patients with low-risk PCa, without a previous transurethral resection of the prostate (TURP) and with a good International Prostatic Symptom Score (IPSS) and a prostate volume < 50 mL. Strong
Use intensity-modulated radiation therapy (IMRT) with a total dose of 74-80 Gy or moderate hypo-fractionation (60 Gy/20 fx in four weeks, or 70 Gy/28 fx in six weeks), without androgen deprivation therapy (ADT). Strong
Other options Only offer whole gland treatment (such as cryotherapy, high-intensity focused ultrasound [HIFU], etc.) or focal treatment within a clinical trial setting. Focal therapy (Cryotherapy, HIFU, laser etc) should only be offered within clinical trial setting Strong
VI.8.2 Guidelines for treatment of intermediate risk disease
VI.8.2.1 Surgery radical prostatectomy (RP)
  • Based on SPCG-4 and PIVOT RCT comparing RRP vs. WW, Prostate Cancer Specific Death rate and Overall All-cause Mortality rate was significantly lower with RP than WW in the SPCG-4 and PIVOT respectively
  • The risk of having positive LNs in intermediate-risk PCa is between 3.7-20.1% (66).
  • An eLND should be performed in intermediate-risk PCa if the estimated risk for pN+ exceeds 5%. (67)

VI.8.2.2 Radiotherapy
The recommended treatment is IMRT or VMAT at an escalated dose (76-80 Gy) or a combination of IMRT or VMAT to optimize radiation dose to tumor and reduce damage to the surrounding organs.

Short-term ADT (4-6 months) is recommended with radiotherapy (68-70). Brachytherapy may be used in combination with radiotherapy in patients with intermediate and high risk prostate cancer if available.

Table VI:20 Recommendations for Intermediate-Risk Disease

Treatment

Recommendation

Strength Rating
Active surveillance Offer AS to highly selected patients (< 10% Gleason pattern 4) accepting the potential increased risk of further metastases. Weak
Radical prostatectomy (RP) Offer RP to patients with intermediate-risk disease and a life expectancy > 10 years. Strong
Offer nerve-sparing surgery to patients with a low risk of extracapsular disease after counseling the patient. Strong
Extended pelvic lymph node (LN) dissection (ePLND) Perform an ePLND in intermediate-risk disease if the estimated risk for positive LNs exceeds 5%. Strong
Radiotherapy Offer EBRT to patients with a life expectancy <10 years or not fit for or refusing surgery Strong
For external-beam radiation therapy (EBRT), use a total dose of 76-78 Gy or moderate hypofractionation (60 Gy/20 fx in four weeks or 70 Gy/28 fx in six weeks), in combination with short-term neoadjuvant plus concomitant ADT (four to six months). Strong
Offer LDR brachytherapy to selected patients; patients without a previous TURP, with a good IPSS and a prostate volume < 50 mL. Strong
In patients not willing to undergo ADT, use an escalated dose of EBRT (76-80 Gy) or a combination with brachy- therapy. Weak
Other therapeutic options Only offer whole gland treatment (such as cryotherapy, HIFU, etc.) or focal treatment within a clinical trial setting. Strong
Do not offer ADT monotherapy to intermediate-risk asymptomatic men unable to receive any local treatment Strong
VI.8.3 Guidelines for treatment of high risk disease
Patients with high risk prostate cancer should be adequately counseled on the possibility of local failure as well as risk distant metastases after initial treatment and a multidisciplinary management of high risk prostate cancer is recommended.

VI.8.3.1 Surgery
Patients with high-risk PCa are at an increased risk of PSA failure, need for secondary therapy, metastatic progression and death from PCa. Nevertheless, not all high-risk PCa patients have a uniformly poor prognosis after RP. (71)

Radical prostatectomy may be recommended to patients with surgically fit high risk prostate cancer who have life expectancy of > 10 years and no pelvic lymph node metastases as a part of multimodal treatment with further adjuvant treatment according to final pathological staging.

Extended PLND should be performed in all high-risk PCa cases undergoing RP as the estimated risk for positive LNs is > 5%. (67)

Nerve sparing radical prostatectomy should be avoided in high risk patients for adequate local cancer control especially be extracapsular extension is suspected in imaging studies.

VI.8.3.2 Radiotherapy
Radiotherapy may be recommended for patients with high risk prostate cancer who are surgically unfit for radical prostatectomy, having expectancy <10 years as a part of multimodal treatment.

For high-risk localized PCa, use a combined modality approach, consisting of dose-escalated IMRT or VMAT, plus long-term ADT FOR 2-3 years.

Patients with local failure after radiotherapy and ADT may need salvage radical prostatectomy.

Table VI:21 Recommendations for High-Risk Disease

Recommendation

Strength Rating
Radical prostatectomy (RP) Offer RP to patients with high- risk localised PCa and a life expectancy of > 10 years (only as part of multi-modal therapy) (Indicate that adjuvant therapy is possible) Strong
Extended pelvic lymph node dissection Perform an ePLND in high-risk disease. Strong
Radiotherapy 1. In patients with high-risk localised disease, use ERBT with 76-78 Gy in combination with long-term ADT (two to three years). Strong
2. In patients with high-risk localised disease, use EBRT with brachytherapy boost (either HDR or LDR), in combination with long-term ADT (two to three years). Weak
3. Do not offer brachytherapy monotherapy to people with high-risk localised prostate cancer. Strong
Other options 1. Do not offer either whole gland or focal therapy to high-risk patients. Strong
2. Do not use ADT monotherapy in asymptomatic patients. Strong
3. Do not offer Active surveillance for high risk prostate cancer Strong
VI.8.4 Guidelines on Locally advanced prostate cancer (LAPC)
VI.8.4.1 Definition
LAPC is defined as histologically diagnosed prostate cancer that extends beyond the prostate gland (cT34); extracapsular extension (T3a), seminal vesicles infiltration (T3b), or invading adjacent organs; bladder or rectum (T4), or any prostate cancer disease with clinically positive pelvic L.N (cN+) regardless PSA level and/or Gleason score with no evidence of distant metastases. (72)

VI.8.4.2 Diagnosis of LAPC
Evaluation of local extension as well as nodal and/or distant metastases is essential for diagnosis LAPC and exclusion of metastatic disease.

VI.8.4.2.1 Comprehensive medical history

Presence of hematuria, bleeding per rectum or hemospermia in patients with high risk prostate cancer may denote locally advanced disease.

VI.8.4.2.2 Digital rectal examination (DRE)

Fixed prostate or hard seminal vesicles during rectal examination may suspect LAPC (T3b/T4 disease).

VI.8.4.2.3 Imaging studies

A cross-sectional contrast study is needed for evaluation of local extension of disease; presence of nodal and/or distant metastases in high risk disease.

VI.8.4.2.4 Pelviabdominal CT with contrast

CT with contrast may be used to detect nodal as well as distant metastases. Serum PSA level, Gleason score and clinical T-stage were statistically significant independent predictors for positive CT finding. (73)

VI.8.4.2.5 Multiparametric magnetic resonance imaging (mpMR)

mpMRI has a high negative predictive value for extracapsular extension (74) and is equivalent to pelviabdominal CT for pelvic L.N staging (75)

VI.8.4.2.6 99mTc-Bone Scan

Bone scan can detect bony metastases with sensitivity and specificity of 79% and 83% respectively (76). Bone scan should be done in patients with T1 with PSA > 20, T2 with PSA >10, patients with T3/T4, GS ≥8 or symptomatic patients. (77)

VI.8.4.2.7 Whole body MRI scans

It is indicated in cases of indeterminate bone metastases. MRI has very high sensitivity and specificity for detection of bone metastases (98-100%) overperforming bone scan in detection of bony metastases. (78)

VI.8.4.2.8 Positron emission tomograpgy (PET) scan

VI.8.4.2.8.1 Sodium Fluroide (18F-NaF) PET

has similar specificity but higher sensitivity to bone can, but cannot detect L.N or visceral metastases (79,80)

VI.8.4.2.8.2 Choline PET

is less sensitive but more specific than bone scan in detection of bony metastases (76). Moreover, it can detect L.N and visceral metastases.

VI.8.4.2.8.3 Prostate-specific membrane antigen-based (68Ga-PSMA) PET

It may play a role in initial staging of prostate cancer in selected cases (higher detection of metastases compared to bone scan and CT. (81)

Table VI:22 Recommendations for Locally advanced prostate cancer (LAPC)

Recommendation

Strength Rating
1. Comprehensive history and digital rectal examination may suspect locally advanced disease Strong
2. Cross-sectional pelvi-abdominal imaging and bone scan should be used for metastatic workup evaluation Strong
3. mpMRI is equivalent to CT in detection of clinically positive lymphadenopathy (cN0) Strong
4. Use PSMA-PET CT or whole body MRI in case of indeterminate bony lesions in bone scan Weak
5. Use of PSMA-PET scan is currently not recommended at initial staging of Prostate cancer Strong
VI.8.4.3 Initial treatment of LAPC
A multidisciplinary management by urologists, medical and radiation oncologists should be adopted.

To date, there is no standard local treatment for LAPC; however multimodal treatment incorporating local and systemic therapies can provide better outcomes in generally fit patients with life expectancy ≥ 10 years. (82)

Patients with LAPC should be counseled on various available treatment modalities, oncological outcomes as well as treatment related complications especially urinary continence and sexual dysfunction.

Table VI:23 Recommendations for Initial treatment of LAPC

Recommendation

Strength Rating
1. Counsel patients with LAPC on various available treatment modalities at multidisciplinary meeting including urologists, medical and radiation oncologists. Strong
2. Local as well as systemic therapy are usually needed in patients with LAPC as parts of multimodal therapy Strong
VI.8.4.3.1 Radical prostatectomy (RP)

Surgical intervention for LAPC (cT3) with no clinically detectable lymph node involvement (cN0) as part of a multimodal therapy in relatively young fit patients can be recommended in high-volume centers (83). Laparoscopic RP may achieve comparable soncological outcomes to open RP in high volume centers, however open RP is preferred over laparoscopic and robotic approaches in LAPC.

Extended pelvic lymph node dissection (eLND) with dissection up to the common iliac arteries should be done in all patients with high risk or LAPC. (84)

Patients with LAPC should be informed for possibility of positive surgical margins and further adjuvant hormonal and/or radiotherapy (RT). PSA monitoring after radical prostatectomy is essential for prompt detection of candidates for salvage RT.

Table VI:24 Recommendations for Radical prostatectomy in LAPC

Recommendation

Strength Rating
1. Discuss open radical prostatectomy as a part of multimodal therapy for selected patients with LAPC (cT3); younger patients with no medical co-morbidities Strong
2. Offer only open radical prostatectomy for LAPC (cT3) in centers with high volume disease and surgical expertise as part of multimodal therapy Strong
3. Laparoscopic radical prostatectomy should be offered to patients with LAPC (cT3) only at high volume centers and could achieve comparable oncologic outcomes Strong
4. Nerve sparing radical prostatectomy is not recommended in the setting of LAPC. Strong
5. Extended pelvic lymph adenectomy should be done during radical prostatectomy Strong
VI.8.4.3.2 Radiotherapy (RT)

One of the treatment options of locally advanced prostate cancer, is combined neoadjuvant / concomitant and adjuvant ADT with radiation therapy, with 24-36 months of adjuvant ADT, this protocol improves disease free survival, metastatic free survival and overall survival especially in patients with GS 8-10. (85)

Radiation therapy preferably with new techniques for instance Intensity modulated radiotherapy (IMRT) and Volumetric-modulated arc therapy (VMAT) can be delivered either by conventional fractionation 78-80 Gy over 39-40 fractions or hypo-fractionated schemes 60 Gy over 20 fractions or 72 Gy over 30 fractions. (86)

In locally advanced disease in patients with good performance status chemotherapy in addition to ADT and radiation could be a valid option as it improves the PFS and marginally improves the OS. (87)

For patients with lymph node positive disease, the addition of radiation therapy to the standard of care (ADT) improves both overall survival and prostate cancer specific survival, so it is recommended to add radiotherapy to either long term ADT and lifelong ADT. (88)

In patients with LN positive disease the addition of abiraterone acetate to radiotherapy and ADT improves OS and failure free survival. (89)

Patients with locally advanced disease who underwent radical prostatectomy should receive adjuvant radiotherapy

if they have high risk features including positive margin, positive LNs, extracapsular extension or detectable PSA. (90)

Patients with pLN positive disease should receive adjuvant ADT in combination with radiation therapy. (89Patients with pLN positive disease should receive adjuvant ADT in combination with radiation therapy. (89)

Recommendations for Radiotherapy in Locally advanced prostate cancer (LAPC)

Recommendation

Strength Rating
1. Discuss radiotherapy in combination with ADT as alternative for radical prostatectomy in surgically unfit patients or patients refusing surgical intervention Strong
2. Radiotherapy should be delivered with the highest available technique when feasible with either conventional dose not less than 76 Gy or hypo-fractionated schedule 60-72 Gy Strong
3. Adjuvant ADT after radiotherapy should be continued for 24-36 months Strong
4. Patients with clinically positive LNs should receive radiotherapy plus ADT as standard of care Weak
5. Patient with LAPC should receive adjuvant radiation after RP if they have any high-risk features (SV involvement, pLN +, ECE or detectable PSA) Strong
6. Offer adjuvant ADT with RT for patients with pathological LN+ after RP. Strong
7. Offer RT with adjuvant ADT for LAPC after RP in patients with other risk factors rather than pLN + (SV involvement, ECE or detectable PSA). Strong
VI.8.4.3.3 Androgen deprivation Therapy (ADT)

Combined RT and ADT is recommended for LAPC; especially with positive nodal involvement.

ADT alone should be only offered to patients with LAPC refusing or unable to receive local treatment (radical prostatectomy or RT) with PSA-doubling time < 12 months or a PSA > 50 ng/mL, or a poorly differentiated tumor. (91)

Table VI:26 Recommendations for Androgen deprivation therapy (ADT) in LAP

Recommendation

Strength Rating
1. Offer ADT in combination with radiotherapy in surgically unfit patients or patients refusing surgical intervention Strong
2. Only offer ADT monotherapy to selected patients refusing or unfit for radical prostatectomy and radiotherapy; who are either symptomatic or asymptomatic, but with a PSA-doubling time (DT) < twelve months or a PSA > 50 ng/mL, or a poorly differentiated tumor. Strong
VI.8.4.3.4 Active surveillance (AS) and watchful waiting

AS should never be offered to patients with high risk prostate cancer or LAPC due to high risk of disease progression and distant metastases

Watchful waiting with deferred ADT monotherapy could be offered to asymptomatic LAPC patients with a PSA-DT > twelve months, a PSA < 50 ng/mL and well differentiated tumor, who are unwilling or not candidates for radical prostatectomy or RT. (92)

Table VI:27 Recommendations for Active surveillance (AS) and watchful waiting in LAP

Recommendation

Strength Rating
1. Do not offer AS for patients with LAPC Strong
2. Watchful waiting with deferred ADT monotherapy may be offered to asymptomatic patients with a PSA-DT > twelve months, a PSA < 50 ng/mL and well differentiated tumor refusing local therapies. weak
VI.8.4.3.5 Adjuvant treatment after initial management of LAPC

VI.8.4.3.5.1.1 No nodal metastases (pN0) after RP with ePLND

Adjuvant RT to the surgical field should be offered to patients at increased risk of local relapse: pT3-4 pN0 with positive margins (highest impact), and/or invasion of the seminal vesicles. (93-95)

No role for prompt Adjuvant ADT in pN0 LAPC for patient who underwent radical prostatectomy and ePLND.

VI.8.4.3.5.2 L.N metastases (pN+) after RP with ePLND

Early adjuvant ADT in pN+ after RP for LAPC improves CSS and OS. (96)

Patients with pN+ disease after an ePLND, should be counseled for adjuvant therapy based on nodal involvement characteristics:

  • Offer adjuvant ADT for node-positive (pN+).
  • Offer adjuvant ADT with additional radiotherapy.
  • Offer observation (expectant management) to a patient after ePLND and < 2 nodes with microscopic involvement, and a PSA < 0.1 ng/mL and absence of extranodal extension. (97)

Table VI:28 Recommendmations for Adjuvant treatment after initial management of LAPC

Recommendation

Strength Rating
1. Do not offer neoadjuvant ADT for patients with LAPC Strong
2. Offer adjuvant RT for selected patients with LAPC and positive surgical margins Strong
3. Counsel patients with pN+ who underwent ePLND for further management; adjuvant ADT, Adjuvant ADT with RT or expectant management (≤2 L. N+ with microscopic involvement, PSA <0.1ng/ml and no extra nodal involvement) Strong
VI.9 Management of biochemical recurrence after primary treatment
VI.9.1 Biochemical recurrence after initial radical prostatectomy
VI.9.1.1 Definition:
Biochemical recurrence after radical prostatectomy defined as patients who achieve an undetectable PSA level after radical prostatectomy with subsequent detectable PSA level that increases on 2 or more subsequent measurements more than 0.2 ng/ml (recurrent disease); or patients with PSA level didn’t fall to undetectable levels after RP (persistent disease). (98,99)

VI.9.1.2 Diagnostic workup
1. Calculation of PSA doubling time for prognosis and risk stratifications (100)
2. Prostate imaging: MRI
3. Bone imaging: Bone scan / 18F PET/CT – 11C PET/CT. (101)
4. Chest, abdomen and pelvis CT.
5. If available and negative conventional imaging, consider 68Ga PSMA PET/CT. (102)
6. Biopsy if imaging revealed prostate bed recurrence.

VI.9.1.3 Treatment options
VI.9.1.3.1 Salvage radiotherapy:

For men with a greater than 10-year life expectancy, which is the vast majority of men with BCR, PSADT less than 6 months, early salvage radiotherapy improves PFS, 5 years and 10 years bRFS, the definition of early salvage RT in controversial, but AUA recommend starting salvage RT while PSA is less than 1 ng/ml, many other studies recommend starting salvage radiotherapy while PSA between 0.2 – 0.5 nd/ml. (103,104)

Radiotharapy dose: 64 – 71 Gy. (105)

Radiotherapy field: Prostate bed ± pelvic LNs. (106)

VI.9.1.3.2 ADT with salvage radiotherapy:

Both bicalutamide 150 mg for 24 months or LHRH agonist for 6 months with SRT is valid options. (107,108)

VI.9.1.3.3 Observation:

Patients with life expectancy less than 5 years and PSADT more than 6 months may be considered for observation as they are unlikely to benefit from SRT. (99)

VI.9.2 Biochemical recurrence after initial Radiotherapy:
VI.9.2.1 Definition of BCR after RT
BCR is defined as any PSA increase greater than or equal to 2 ng/mL higher than the PSA nadir. (109)

VI.9.2.2 Diagnostic workup
The same as BCR after radical prostatectomy.

VI.9.2.3 Treatment options:
  • Radical prostatectomy. (110)
  • Cryotherapy. (111,112)
  • High-Intensity Focused Ultrasound (HIFU). (113)
  • ADT: both continues and intermittent ADT (114,115)
  • Brachytherapy. (116,117)
  • Observation: especially in patients with negative TRUS biopsy.

Table VI:29 Recommendations for Management of biochemical recurrence after primary treatment

Recommendation

Strength Rating
1. BCR after radical prostatectomy defined as either detectable PSA after 4 – 6 weeks post-operatively or detectable PSA level more than 0.2ng/ml in two consecutive measurements after undetectable PSA. Strong
2. BCR after definitive radiotherapy ± hormonal therapy defined as PSA increase more than 2 ng/ml after nadir. Strong
3. Diagnostic and metastatic workup should include bone scan, CT chest, pelvis and abdomen. Strong
4. In highly selective patients, with doubtful conventional imaging results and long-life expectancy we can consider 68Ga PSMA PET/CT. Weak
5. Treatment for patients with BCR after RP, patients should be stratified according to life expectancy and PSADT. Strong
6. For patients with life expectancy less than 5 years and PSADT more than 6 months, observation should be considered the preferred option. Strong
7. For patients with life expectancy more than 5-10 years and PSADT less than 6 months, treatment should be started as early as PSA level less than 0.5ng/ml. Strong
8. Treatment should include salvage radiotherapy to dose between 64-72 Gy Strong
9. Addition of hormonal treatment together with salvage/adjuvant radiation in rapidly progressing disease, either LHRH agonist for 6 months or in patients with concern regarding the toxicity of LHRH agonist we may consider bicalutamide for 24 months or no hormonal treatment. Weak
10. Treatment of patients with BCR after definitive RT ± hormonal treatment, patient should be stratified according to life expectancy, performance status and their understanding and accepting of different toxicities. Strong
11. Observation may be considered in patient with short life expectancy and patients with negative TRUS biopsy. Strong
12. Radical prostatectomy is a valid option for selective fit, young patients with long life expectancy (more than 10 years) and no major comorbidities after counseling them with the expected urinary and sexual toxicities. Strong
13. High-Intensity Focused Ultrasound (HIFU), may be considered in selected cases in experienced centers when trans-perineal template prostate mapping (TPM) is available or multi-parametric MRI with matched TRUS biopsies, especially in patients with concerns regarding bowel and urinary toxicities. Weak
14. Brachytherapy and cryotherapy are alternative options, but due to lack of centers providing both modalities and expected cost, both options may be considered in selected patient when feasible centers are available. Weak
15. Androgen deprivation therapy should be considered in patient not eligible for RP or not accepting its toxicities, especially with PSADT less than 6-9 months, those patients should start early ADT within 8 weeks of diagnosis of BCR, and intermittent ADT should be discussed with the patient to decrease the like hood of ADT toxicities. Strong
16. Patient must be counseled and discussed in each management step, and receive clear, understandable information about the pro and con of each treatment option, and the patient preference must be taken seriously in the treatment decision. Strong
17. Counseling the patient regarding radiation toxicity, emphasizing on rectal and sexual toxicity is a fundamental step before proceeding for radiotherapy Strong
18. Counseling the patient regarding radical prostatectomy toxicity, emphasizing on urinary incontinence, sexual toxicity and quality of life is a fundamental step before proceeding for surgery. Strong
VI.10 Management of Metastatic Hormone Sensitive Prostate Cancer (mHSPC):
VI.10.1 Introduction & Evidence Based Medicine:
Since Charles Huggins established the critical role of androgens in stimulating prostate cancer growth in 1941, androgen deprivation therapy (surgical or medical) was considered to be the primary management of advanced/metastatic prostate and maintained to be the cornerstone of effective therapy across decades in all guidelines (118,119). Many controversial issues do exist regarding the intermittent versus continuous (most commonly adopted) ADT, while immediate treatment upon diagnosis is generally preferred to delayed onset treatment due to the survival advantage. (120,121)

Despite of being palliative in metastatic disease state, ADT can normalize serum levels of prostate-specific antigen (PSA) in over 90 percent of patients and can produce objective tumor responses in 80 to 90 percent with antitumor activity improving quality of life by reducing pain and other disease related complications, however, the duration of response is highly variable, and most prostate cancer patients eventually experience disease progression into castrate resistant disease with ultimate fatality. The development of additional therapies; cytotoxic therapies & androgen receptor targeting agents (ARTA) with survival advantage, has led to their earlier use in combination with ADT for initial therapy of metastatic disease aiming at improving castration quality to achieve positive influential effect on survival outcome. (122)

In the recent years with incorporation of chemotherapeutics and ARTA early in the upfront treatment of mHSPC, there is a growing emphasis upon defining the subset of patients who could gain the maximum benefit in terms of median Overall Survival based on the tumor burden or volume present (High versus low), where many definitions were existing based on clinical trials populations as shown in below (Table VI:30).

Table VI:30 Definition of high & low disease volume used in different clinical trials adding chemotherapy or ARTA to ADT for upfront management of mHSPC

Trial

High Volume

Low Volume
Glass et al Extensive Disease:
Appendicular skeletal metastases and/or visceral metastases		 Minimum Disease:
Nodal and/or axial skeletal metastases
CHAARTED Trial >4 bone metastases with one or more outside the vertebral bodies and pelvis and/or visceral metastases (Extranodal) All others
STAMPEDE Trial Same as the CHAARTED trial Same as the CHAARTED trial
GETUG-AFU15 Same as the CHAARTED trial Same as the CHAARTED trial
LATITUDE Trial 2 or more the following: Visceral metastases, >3bone metastases, Gleason score > 8 Only one of the following: Visceral metastases, > 3 bone metastases, Gleason Score > 8
Moreover, and more recently, a newer term applied for those patients with oligometastatic disease (OMPC) aiming at exploring the role of local therapy namely radiation therapy plus ablation of the few number of lesions present in metabolic while not seen in conventional imaging. However, more controversial issues emerged for the definition and how to diagnose oligometastatic disease as shown in table 30 (123,124). The most widely accepted definition of OMPC is "The low-volume tumor burden up to 3–5 metastases in bone and/or lymph nodes on conventional imaging". (125)

Table VI:31 Different definitions used to describe oligometastatic Mhsp

Study

Cutoff Number of Oligometastases

Location of Metastases

Imaging Modality
Singh et al < 5 Any Isotopic Bone Scan
Berckovic et al < 3 Bone or L. N Isotopic Bone Scan, Choline and FDG PET/CT
Schick et al < 4 NR Isotopic Bone Scan, Choline and FDG C-Acetate/CT
Decaestecker et al < 3 Bone or L. N FDG and Choline PET/CT
Jereczek-Fossa et al 1 L.N FDG and Choline PET/CT, CT
Ost et al < 3 Any FDG and Choline PET/CT
Ost et al < 3 Any Choline PET CT Scan
For the time being and based on 6 phase III trials: CHAARTED, LATITUDE, ARCHES, ENZAMET, TITAN & STAMPEDE trials; 4 Agents (Docetaxel, Abiraterone Acetate, Enzalutamide & Apalutamide) were approved to be added to the benchmark ADT for mHSPC in both low and high tumor burden based on overall survival advantage except Docetaxel which showed the benefit only in high tumor burden disease. The choice to add which pharmaceutical is controversial since the pooled data and network meta-analysis failed to show superiority for any in relation to others in terms of OAS. The choice between the recently approved agents (All are Category 1 Evidence) plus ADT can be suggested based on many factors as duration of treatment, profile of anticipated complications and disease parameters as shown in table 31. (126)

Table VI:32 How to choose between up-front treatments in mHSPC

DOCETAXEL

ABIRATERONE

ENZALUTAMIDE /APALUTAMIDE
Duration of Treatment Short term Long term Long term
Toxicities Peripheral neuropathy, hair loss, nail changes Liver enzymes & Electrolytes Seizures, Falls
Corticosteroids Yes Yes No
Settings High Tumor Burden Any Any
In developing countries with low national financial resources, the most cost effective treatment should be elected as an up-front treatment of mHSPC. Based on a recent publication by EUA, ADT plus Docetaxel is considered to most cost benefit effective as compared to ADT plus Abiraterone Acetate despite modest superiority of Abiraterone Acetate in network meta-analysis. (127)

A consensus on management of OMPC in daily clinical practice is limited by scarcity of evidence from clinical studies. Phase 3 STAMPEDE trial had shown significant difference in terms of Failure Free but not Overall Survival. Management is best within the context of clinical trial or via Multidisciplinary Team approach where the facility of PSMA PET CT Scan should be present. Management of OMPC via external beam radiation therapy to the primary and ablative radiation therapy to few metastatic lesions detected only by PSMA PET CT can be considered. It is included under management of low tumor burden mHSPC in NCCN guidelines while not specified in EUA guidelines. (128,129)

Suggested National Guidelines for The Management of Metastatic Hormone Sensitive Prostate Cancer (mHSPC), (Table VI:33)

Table VI:33 Summary of therapeutic interventions according to the clinical situation and according to level of national recommendations

Clinical Situation

Intervention

Strength Rating
  • mHSPC
  • Low volume of Disease)
  • Asymptomatic
 Immediate and Continuous ADT Strong
Delayed ADT* Weak
Intermittent ADT* Weak
  • mHSPC
  • (Low Volume of Disease)
  • Symptomatic
 Immediate and Continuous ADT plus ARTA (Abiraterone Acetate, Enzalutamide or Apalutamide) Strong
Palliative External Beam Radiation Therapy Strong
  • mHSPC
  • High Volume of Disease
  • Symptomatic or Asymptomatic
 Docetaxel Strong
ARTA**:
  • RTA**dedico Acetate
  • cetateoedico
  • edicoeoedicor
 Strong
Palliative External Beam Radiation Therapy (in Symptomatic osseous disease) Strong
* Certain clinical situations
** Approved upon tumor board in treating tertiary center for certain clinical and re-embarrassment situations.
1. Achieve castrate level of serum testosterone (< 50 ng/ml): (Category 1)
  • Immediate onset of treatment unless:
    a. Life expectancy is < 5 years.
    b. Asymptomatic patient.
    c. The presence of uncontrolled comorbid disease (Cardiac, Central Nervous, Metabolic disorders).
  • Continuous ADT is generally preferred to intermittent approach unless the patient is welling for non-continuous treatment and having low tumor volume, asymptomatic and well informed about the pros and cons of having continuous treatment.
  • Surgical versus medical castration (LHRH agonists and antagonists) is to be decided following discussion with the patient taking into consideration the cost of treatment, patient’s compliance and well.

2. Adding Approved Agents with Survival Advantage:

Based on extent of volume of systemic disease:

a. Low Tumor Volume:
  • Careful monitoring by serum testosterone and PSA every 3 months after the nadir. (Preferred)
  • Palliative external beam radiation therapy in a symptomatic patient.
  • In symptomatic patients, also ARTA can be considered:
    i. Abiraterone Acetate (Category 1)
    ii. Enzalutamide (Category 1)

b. High Tumor Burden:
  • Docetaxel 75 mg/m2 every 21 days for 6 courses provided of adequate hematological recovery and within normal ranges organ functions especially symptomatic patients with rapidly progressing disease and the presence of visceral metastases. (Preferred – Based on Cost Benefit Study).
  • ARTA with survival advantages can be considered:
    i. Abiraterone Acetate (Category 1)
    ii. Enzalutamide (Category 1)
    iii. Apalutamide (Category 1)

The use of 1st generation anti-androgen (e.g. Bicalutamide) is only used currently for a month with the start of LHRH analogue to prevent flare phenomenon, however it can be used according to local authority and tumor board in a tertiary service center based on the economic issues (National Practice).

Palliative EBRT is still a valid option for persistent bony pains due to metastases.

3. Special Situations:

Patients proven to have few metastatic sites by PSMA – PET Scan after being negative in conventional imaging (Oligometastatic Disease):
  • Continue on ADT only (Preferred).
  • If within the context of Clinical Trial or MDT approach; local EBRT to primary tumor and ablative SBRT to metastatic sites (Optional).

Patients should be considered to have bone-remodeling agents (Zoledronic Acid or Denosumab) to protect against therapy associated bone loss every 3 – 6 months with Calcium and Vitamin D supplementation to reduce skeletal related events.

If an impending fracture or spinal cord compression would be encountered, a prophylactic surgical fixation should be attempted without delay.

The help of clinical nutritionist, physiotherapist and psychiatrist would be highly appreciated to maintain the quality of life particularly with hormonal manipulation.

Careful attention should be given to the drug to drug interactions between the anti-neoplastic agents and the commonly used medications in this age group.

Follow up strategy included regular serum Testosterone and PSA every 3 months unless otherwise indicated due to new or recurring symptoms to detect evolution of castrate resistant phase, while radiologic images would be attempted if serum PSA started to show successive rises or clinical suspicion of having a complicated or progressing case.

VI.11 Castration-resistant Prostate Cancer (CRPC)
VI.11.1 Definition of Castration-resistant PCa
Ensure a castrate serum testosterone < 50 ng/dL plus either;

a. Biochemical progression: Three consecutive rises in PSA one week apart resulting in two 50% increases over the nadir, and a PSA > 2 ng/mL or,

b. Radiological progression: The appearance of new lesions: either two or more new bone lesions on bone scan or a soft tissue lesion using RECIST (Response Evaluation Criteria in Solid Tumours) (130,131)

Table VI:34 Castrate-resistant disease definition

Recommendation

Strength Rating
Ensure testosterone levels are < 50 ng/dL to diagnose CRPC Strong
VI.11.2 Non-metastatic castration-resistant PCa
VI.11.2.1 Definition:
The occurrence of biochemical progression with no overt clinical metastases detected via bone scan and CT-scan (conventional imaging as referred to in APCCC) (132) remains till now the standard description for this state.

Next-generation imaging (NGI), positron emission tomography [PET], PET/CT, PET/MRI, or whole-body MRI) can be offered in M0CRPC if a change in management is anticipated but data in this area remains scarce. (133)

Eventually, progression to an evident metastatic state occurs in a third of the M0CRPC patients within 2 years. Risk factors for converting to a metatstatic state are a high PSA and a rapidly rising PSA. (134)

In patients with unfavorable PSA kinetics (doubling time ≤10 months during continuous ADT and total PSA level ≥2 ng/ml) and nonmetastatic by conventional imaging 3 randomised phase 3 clinical trials (PROSPER, SPARTAN, and ARAMIS) have identified new treatment standards for patients with M0 CRPC (135-137) with the addition of enzalutamide, apalutamide, or darolutamide to on-going ADT. The metastasis free survival (MFS) and recently OS were met by all 3 trials and severe toxicity was low. Most patients (around 70%) in the 3 trials had a DT ≤ 6 month making this group of higher bearing to receive these novel therapies, but generally it was beneficial in the whole cohort. At the moment darolutamide is not available in Egypt and thus was not included in the current recommendations, (Table VI:35)

Table VI:35 Recommendations for Non-metastatic castrate-resistant disease

Recommendations

Strength Rating
1. Propose apalutamide or enzalutamide to patients with M0 CRPC with a PSA-DT≤ 6 months and a high risk of developing metastasis Strong
2. Propose apalutamide or enzalutamide to patients with M0 CRPC with a PSA-DT 6 to≤ 10 months and a high risk of developing metastasis Strong
VI.11.3 Metastatic castration-resistant PCa
Ultimately men with PCa will progress despite castration. Despite this, androgen suppression should be continued in these patients. The treatment landscape here is affected by previous incorporation of agents into the castration naïve phase or M0CRPC. Furthermore, it is even more challenging to sequence approved therapies and sometimes logistics have the upper hand in this decision.

VI.11.3.1 First-line treatment of mCRPC abiraterone, enzalutamide, docetaxel, Sipuleucel-T
The first line options have earned their place through prospective randomized phase 3 trials against comparators that are currently not considered standard of care. A survival benefit was appreciated in asymptomatic men with abiraterone, enzalutamide, and sipuleucel-T, radium-223 in symptomatic men with bone metastases and docetaxel in either asymptomatic or symptomatic cases. (138-147)

Sipuleucel-T is not available outside the USA, whilst radium-223 is not available in Egypt. (Not included in table 31)

In an expert consensus conference half of the panellists regarded bicalutamide and dexamethasone inappropriate for treating mCRPC if abiraterone and enzalutamide are available. (148)

Thus recognizing the financial constraints internationally and locally it would seem wise to propose these measures in the context of limited resources only if life prolonging agents were not available by any means with docetaxel use being encouraged in fit chemo-naive patients as a more economic approach when feasible.

VI.11.3.2 Second-line treatment for mCRPC
Progression in mCRPC unfortunately is inevitable and only prospective randomised data for second-line treatment in men who have received docetaxel as first-line treatment for mCRPC. Abiraterone, cabazitaxel, enzalutamide, and radium-223 have demonstrated an OS benefit. (147, 149-153)

* Cabazitaxel

A reduced dose of 20 mg/m² cabazitaxel was found to be equivalent in OS to 25 mg/m², but less toxic. Hence, the lower dose should be selected in the second-line setting. (149)

Treatment post- docetaxel / one line of hormonal treatment for mCRPC

Third line treatment after docetaxel and a single hormonal treatment for mCRPC is generally less beneficial than with earlier use (154,155). Given the possible evidence of cross-resistance between enzalutamide and abiraterone, radium-223 or cabazitaxel seem to be valid choices. Docetaxel rechallenge may be considered. (156-158)

Third-line treatment with either cabazitaxel or alternative AR-targeted therapy (enzalutamide or abiraterone) in post- docetaxel patients whose mCRPC had progressed rapidly (within a year) on their first AR-targeted therapy was addressed by the CARD trial and results seemed to favor cabazitaxel use. (159)

In the era of precision medicine and the quest for an actionable target has indeed extended to PC. (160) Guidelines such as the NCCN currently recommend considering tumour genomic profiling for patients with regional or metastatic disease. These include tests for microsatellite instability (MSI)/defective mismatch repair (dMMR), and for variants involving other DNA repair genes, such as BRCA1/2, PTEN, ATM and CDK12. (138)

Men possessing somatic homologous recombination deficiency (HRD) exhibited high response rates, up to 88%, with polyADP-ribose polymerase (PARP) inhibitors in the post docetaxel and at least one novel hormonal agent arena. [32] Regulatory approval was obtained for olaparib after a significant clinical benefit to men with BRCA1/2 or ATM-mutated mCRPC was demonstrated. (162)

Alternatively, Platinum based chemotherapy may be offered to patients unable to receive a PARP inhibitor in the setting of limited resources but studies are needed to substantiate this use. (138)

Deficient MMR or MSI high mCRPCmay be given pembrolizumab if feasible. (138)

Neuroendocrine prostate cancer (NEPC) development may be suspected if progressive disease with frequent visceral metastases is encountered with a low or moderately elevated serum PSA. This aggressive variant has a poor prognosis and requires tissue biopsy to confirm its diagnosis. Similarly, to small-cell lung cancer, platinum- based chemotherapy regimens may be deployed in therapy as it does not express the androgen receptor rendering it hormone refractory. (138, 163)

VI.11.4 Monitoring of treatment
After thorough baseline history and clinical examination necessary laboratory values are noted (PSA, FBC, KFT, LFTs, ALP) along with a bone scan and CT of chest, abdomen and pelvis. (148)

The incorporation of novel imaging such as Choline or PSMA PET CT scans for progressing CRPC is probably not as beneficial as in cases with BCR or hormone naïve disease and remains ill defined. (130,148)

Additionally, relying on PSA solely to monitor CRPC may be misleading as visceral metastases have been recorded in cases lacking PSA elevation or neuroendocrinal differentiation. (164,165)

This led expert recommendations from the PCWG2 and APCCC to use a combination of bone scintigraphy, CT scans, PSA level and clinical benefit in evaluating men with CRPC, with the later stressing the need for radiological assessment even in the absence of clinical indication at least every 6 months. (148, 166)

VI.11.5 When to change treatment
At least two of the three criteria (PSA progression, radiographic progression and clinical decline) should be fulfilled to discontinue treatment. (166)

VI.11.6 Bone metastases/bone Health in CRPC
Painful bone metastases are common in CRPC. Surgical intervention is warranted in case of spinal cord compression (if feasible) which is considered an oncological emergency, along with high dose corticosteroids and subsequent external beam radiotherapy. Radiotherapy plays an integral part in skeletal secondaries and may be given as a single dose or multiple fractions. (167,168)

VI.11.7 Preventing skeletal-related events
VI.11.7.1 Bisphosphonates
Zoledronic acid has been evaluated in mCRPC to reduce skeletal-related events (SRE), however prospective trials failed to demonstrate a survival benefit. (169)

VI.11.7.2 RANK ligand inhibitors
The efficacy and safety of denosumab vs. zoledronic acid in metastatic CRPC was initially found to be superior in delaying or preventing SREs in a phase III trial but later a post-hoc review of these end-points found denosumab displayed identical results. (170,171) Again, these findings were not associated with any survival benefit.

The potential toxicity (e.g., osteonecrosis of the jaw) of these drugs must always be kept in mind (5-8.2% in M0 CRPC and mCRPC, respectively) and monitoring of serum calcium and renal function is necessary (172). Thorough dental examination before initiating therapy for fear of jaw necrosis is obligatory as it is increased by a history of trauma, dental surgery or dental infection. Preventative treatment is advised with these agents (e.g. supplemental calcium, Vitamin D) and for SRE in CRPC patients. (130)

Table VI:36 Recommendations of Metastatic castrate-resistant disease therapies & supportive care

Recommendations

Strength Rating
1. Treatment with life-prolonging agents should be encouraged if available.
First-line therapy choice depends on the performance status, symptoms, comorbidities, location and extent of disease, patient preference, previous treatment in the hormone-sensitive metastatic PCa (HSPC) phase (alphabetical order: abiraterone, docetaxel, enzalutamide,). 		Strong
2. Treat eligible patients with docetaxel Strong
3. Second-line treatment options if available for mCRPC rely on pre-treatment performance status, symptoms, patient preference, comorbidities and extent of disease (alphabetical order: abiraterone, cabazitaxel, docetaxel and enzalutamide. Strong
4. Rechallenge with Docetaxel if 1 year interval of disease stability had been achieved and if no other options are suitable/available. Weak
5. Third line cabazitaxel is favoured for men previously treated with docetaxel and progressing within 1 year of therapy on abiraterone or enzalutamide. Strong
6. HRR gene-mutated mCRPC, germline or somatic, after treatment with enzalutamide or abiraterone, and/or a taxane-based chemotherapy may be offered a PARP inhibitor/Olaparib Strong
7. Metastatic CRPC men with bone secondaries require bone protective agents to avoid SRE. Strong
8. Patients on bisphosphonates or denosumab must receive calcium and vitamin D supplementation with regular calcium level and renal function monitoring Strong
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