THE MANAGEMENT OF PROSTATE CANCER . pptx

This PowerPoint is intended for education purposes. To help medical students and registrars in Urology to have in-depth knowledge in a summarized manner about prostate cancer. Also to help practicing urologists to for some quickly reference and knowledge refreshment on prostate cancer and its management. All the information in this PowerPoint is from Campbell Urology 12th edition and EAU 2024 updated guidelines

1. PROSTATE CANCER Dr. Chipili B . Bsc.HB, MBChB, FZCMS (Urology)

2. Dr. Chipili B . “The aim is to cure or stabilize a potentially fatal disease while limiting adverse effects that may arise from the treatment”

3. Epidemiology It is the most common urological cancer in men The life time risk of a 50 year old man having prostate cancer is 40% About 12.5% (1 in 8 ) men alive today will be diagnosed with clinical prostate cancer 2.5% ( 1 in 40) will die from this disease Incidence varies with race and is higher in blacks than whites

4. Risk factors Increasing age Family history (genetic predisposition) Race Prevention No high level evidence shows that preventive measures can reduce the risk of prostate cancer

5. Etiology Prostate cancer arises and progresses from genetic alterations that activate the oncogenes and inactivate the tumor suppressors Both l ow grade and high grade prostate cancers are thought to arise from the common precursor lesion Further genomic alterations determine the pathway to either low grade or high grade disease The exact cause of these genetic alterations is unknown

6. Clinical features Localized prostate cancer is usually asymptomatic Symptoms arises from locally advanced or metastatic disease Locally advanced prostate cancer can present with LUTS or hematuria Metastatic disease presents with a variety of symptoms depending on the organs affected Most common symptoms are lower backache, weakness lower limbs, paraplegia, renal impairment, chest symptoms, anemia etc.

7. The role of androgens Androgens influence the development, maturation and maintenance of the prostate They affect both proliferation and differentiation of the luminal epithelium The primary androgen of the prostate is DHT produced with the help of type 2 5 ά -reductase This enzyme is a prerequisite to normal development of the prostate and external genitalia in males Insufficient exposure of the prostate to DHT appears to protect against prostate cancer development

8. Prostate cancer biomarkers Molecular compounds that assist in predicting the likelihood of prostate cancer PSA is a widely used prostate cancer biomarker It is used for early detection of prostate cancer, risk stratification and monitory prostate cancer post treatment It is prostate specific and not cancer specific Substantially elevated PSA may be due to inflammation or BPH rather than prostate cancer

9. Prostate specific antigen PSA is a serine protease also known as Human Kallikrein (HK) 3 Its main function is to liquify semen through its action on gel forming proteins within semen after ejaculation It is produced in an inactive form as pro-PSA which is activated to PSA by HK2 In serum it circulates in both complexed (cPSA) and free PSA (fPSA) forms cPSA makes up 70% of the total circulating PSA PSA secretion is strongly androgen dependent

10. Prostate specific antigen In the absence of prostate cancer serum PSA varies with age, race and prostate volume On a per cell basis PSA expression in BPH and prostate cancer is similar Elevated PSA levels in serum is due to the disruption of the cellular architecture within the prostate gland (basement membrane/basal layer ) Prostatic trauma causes a sharp spike in PSA that may persist for up to 4 weeks or more before returning to baseline

11. Prostate specific antigen The impact of prostatitis and BPH confounds the accuracy of PSA in prostate cancer screening 5 ά -reductase inhibitors (Finasteride/dutasteride) lower the serum PSA levels by approximately 50% after 6 to 12 months of treatment Interpretation of PSA values should always consider the presence of prostate disease, diagnostic procedures or prostate directed therapies

12. PSA Derivatives Parameters of PSA which are used to further increase the positive predictive value of PSA towards prostate cancer PSA velocity PSA doubling time PSA density Molecular PSA (free to total PSA)

13. Free prostate specific antigen 4 to 45% of PSA in serum exists as enzymatically inactive fPSA PSA produced by prostate cancer more frequently escape the proteolytic processing This results in more serum PSA complexed to ACT and lower free PSA in cancer compared to benign prostate fPSA improves the accuracy of PSA as a prostate cancer screening biomarker It is approved by the FDA for prostate cancer screening in normal DRE and PSA between 4 and 10 ng/mL %fPSA does not change with 5 alpha reductase inhibitors

14. Prostate specific membrane antigen PSMA is a transmembrane glycoprotein found on all prostatic epithelial cells Its expression is elevated in prostate cancer compared to normal prostate tissue Tissue overexpression may confer a worse prognosis in prostate cancer undergoing radical prostatectomy Currently PSMA has greatest use in targeted imaging ⁶⁸Gallium PSMA positron emission tomography (⁶⁸Ga-PSMA PET) is now commonly used imaging for detecting the disease in biochemical recurrence after curative therapy

15. Inherited genetic markers Up to 40 to 50% of prostate cancer risk may be related to familial and hereditary factors BRCA 1 and BRCA 2 mutations have been associated with significant risk of prostate cancer BRCA 2 mutations prostate cancer is usually diagnosed at a younger age, have higher Gleason scores and shorter median survival time than sporadic prostate cancers Testing for single genes such as BRCA1 or BRCA2 are clinically available but multi-gene panel testing is more common in the absence of a known familial mutation

16. Prostate biopsy 12 core TRUS prostate biopsy under local anesthesia is current standard of care technique D igital directed prostate biopsy which was common until the 80’s is still being used in resource limited settings On TRUS cancer lesions usually look hypoechoic but up to 29% are isoechoic and 1 % hyperechoic I ndications for a prostate biopsy are abnormal DRE and elevated PSA Contraindications include significant coagulopathy, severe immunosuppression and acute prostatitis

17. Prostate biopsy

18. Prostate biopsy Prostate biopsy is done with patient in left lateral decubitus with knees and hips flexed at 90⁰ or in lithotomy positions A spring driven 18G needle core biopsy device or biopsy gun is passed through a needle guide attached to the U/S scan probe 6 cores (standard sextant) is currently considered inadequate for routine prostate cancer detection Extended 12 core systematic biopsy (6 to 12 cores) results in significant increase in cancer detection rate Saturation biopsy (18 to 21 cores) does not result in similar increase

19. Prostate biopsy

20. Prostate biopsy Transperineal biopsy offers an approach to the prostate where there is no rectum (Surgical extirpation or congenital anomaly) Advantages of transperineal biopsy are reduced infection, improved identification of apical and anterior tumors It requires extensive anesthesia and has inferior visualization of the prostate which reduces precision for systematic sampling Prostate biopsy is associated with a very low risk (<1%) complications requiring hospitalization Complications include hematuria, rectal bleeding, hematospermia, prostatitis, epididymitis, urinary retention and pyrexia

21. Transrectal vs Transperineal biopsy

22. TRUS/MRI fusion biopsy Combines detailed information from a diagnostic mpMRI and superimposes its images with real time TRUS Pre-biopsy MRI identifies lesions suspicious of cancer based on its multiple parameters (PIRAD scores) The target lesions are delineated and loaded on a software platform TRUS of the prostate is performed with the MRI and real time TRUS images superimposed to allow lesion directed biopsies

23. Prostate cancer pathology Prostate cancer is said to arise from prostatic intraepithelial neoplasm (PIN) PIN consists of structurally benign prostatic glands consisting of cytologically atypical cells It is classified into low grade and high grade PIN The mean risk of malignancy on subsequent biopsy within a year after the diagnosis of HGPIN is about 20 – 30% HGPIN on does not give rise to elevated PSA values Intraductal carcinoma has more cytological atypia than HGPIN

24. Prostate pathology Adenocarcinoma contributes about 95% cancer of the prostate The remaining 5% are heterogenous consisting of epithelial, non epithelial or ectopic in tumors Epithelia carcinoma variants may include; squamous cell, transitional cell, Adenosquamous, neuroendocrine, mucinous, signet ring, small cell, endometrioid etc. Nonepithelial carcinomas are; leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, angiosarcoma, carcinosarcoma and lymphomas Metastatic malignancies to the prostate also contribute to the 5%

25. Prostate cancer grading Grading of prostate cancer is by Gleason scoring system This system is based on the architectural patterns of the glands under low power microscope These patterns are assigned a Gleason grade of 1 to 5 depending on differentiation of the cells The most and second most common patterns are assigned the primary and secondary Gleason grades respectively The Gleason score (sum) is the addition of the primary and secondary Gleason grades

26. Prostate cancer grading The highest pattern if present is assigned a tertiary grade and added to the primary grade to come up with the Gleason score Gleason patterns 1 and 2 are not diagnosed on needle biopsy specimens and are never assigned by the pathologists The lowest Gleason score obtainable is 6 and the highest is 10 Gleason score is the single most powerful predictor of prognosis for prostate cancer The ISUP 2014 divides the Gleason score 7 into two prognostically distinct groups (i.e. 3+4 and 4+3)

27. ISUP 2014/WHO 2022 grade groups

28. Prostate cancer histopathology report The prostate cancer histopathology report confirms presence of malignancy in submitted samples S tates the histological type of carcinoma and parameters describing its extent These parameters include proportion of positive cores, percentage of carcinoma per core and Gleason score Reporting on radical prostatectomy specimen includes the type of carcinoma, global ISUP grade, pathological stage and surgical margin status

29. Prostate cancer staging

30. EAU risk stratification

31. Clinically significant PCa This is prostate cancer that is likely to cause morbidity and mortality It includes the cancer in the intermediate and high risk groups This type of prostate cancer requires treatment Any prostate cancer not likely to cause morbidity or mortality is termed clinically insignificant L ow risk prostate cancer and some low volume ISUP grade group 2 cancers are clinically insignificant Diagnosis and treatment of such cancers lead to overdiagnosis and overtreatment respectively

32. Screening of prostate cancer Screening is early detection clinically inapparent prostate cancer (without clinical features) May be associated with overdiagnosis of the disease Most essential is breaking the link between diagnosis and active treatment of the disease Currently screening of prostate cancer is done by use of serum PSA Screening for prostate cancer is based on individualized risk factors present (i.e. individualized risk adapted strategy) Generally it starts from the age of 55 to 69 years

33. Diagnosis of prostate cancer The clinical diagnosis of prostate cancer is usually suspected based on the DRE and/or PSA levels Definitive diagnosis depends on histopathological confirmation of adenocarcinoma in the prostate from biopsy cores, TURP or TVP Further diagnostic or staging workup is guided by the treatment options available for the patient This takes into account the disease characteristics and patient characteristics Diagnostic procedures that will not affect treatment decision should be avoided

34. Principles of disease management of PCa The management of prostate cancer takes into consideration both the disease and patient characteristics Disease characteristics include clinical staging, grading (risk stratification) and imaging Staging workout using imaging aims at determining whether the disease is organ confined or metastatic Patient characteristics include age, life expectancy and performance status (presence of comorbidities)

35. Treatment options for localized (organ confined) disease A im is to cure the disease provided patient characteristics are suitable For unsuitable patient characteristics treatment is deferred for palliation of symptoms Treatment options are active surveillance, radical prostatectomy, radiotherapy and watchful waiting Active surveillance is the best care option for very low risk and preferable option for most low risk diseases (favorable intermediate) Generally the treatment option for low to intermediate risk disease is monotherapy Multimodal therapy is used in high risk localized and locally advanced

36. Curative treatment options The curative treatment options are radical prostatectomy and radiotherapy No active treatment option superior over the other or deferred active treatment in terms of overall and cancer specific survival Surgery can be done by open, laparoscopic or robotic approaches No single surgical approach is superior in terms of functional and oncological results Radiotherapy can be done by either brachytherapy or external beam radiation therapy

37. Treatment options for metastatic disease The aim of treatment for metastatic prostate cancer is to limit further spread of the disease and prevent it’s serious sequelae Metastatic prostate cancer is always high risk whether asymptomatic or symptomatic The standard of care for metastatic disease is combination systemic therapy This therapy involves the use of androgen deprivation therapy combined (ADT) with any of the following; androgen biosynthesis inhibitors, chemotherapy, newer generation androgen receptor blockers etc.

38. Management of low risk disease Active surveillance is the best care option for low risk disease patients with a life expectance of more than 10 to 15 years and no non-reversible comorbidities Involves PSA every 6 months, DRE every 12 months and a repeat biopsy every 2 to 3 years for 10 years In cases of PSA progression or changes in DRE or MRI findings a repeat biopsy is warranted Intraductal carcinoma is excluded from active surveillance Those with a life expectancy of less than 10 years or have non reversible comorbidities the management option is watchful waiting

39. Management of intermediate risk disease Generally active treatment begins in the intermediate risk group Patients with a life expectancy of more than 10 years and no non-reversible comorbidities are candidates for curative treatments A small subgroup within this group can still benefit from deferred active treatment This subgroup with favorable risk within the intermediate group are preferably offered active surveillance The favorable risk subgroup include patients with ISUP Gleason group 2 and low extent of disease on biopsy and imaging Unfavorable risk subgroup within the intermediate risk are treated with radical prostatectomy or radiotherapy as a monotherapy

40. Management of intermediate risk disease The low extent of disease is defined by; < 10% of Gleason grade 4, ≤ 3 positive cores, ≤ 50% cancer involvement/core The other parameters of risk stratification should be in the low risk group i.e. PSA < 10 ng/mL and ≤ cT2a Men with ISUP grade group 3, a life expectancy of 10 years and no serious comorbidities are given curative treatment as described above Radiotherapy in this group is combined with a short term ADT (4 – 6 months) Those with a life expectancy of less than 10 years or have non reversible comorbidities are put on watchful waiting

41. Management of high risk localized disease Generally curative treatment in this group is multimodal therapy Radical prostatectomy is done together with extended PLND Radiotherapy is coupled with a long term ADT (2 to 3 years) Patients unwilling or unable to receive any form of curative treatment are given ADT monotherapy if they meet the criteria below PSA doubling time < 12 months and either PSA > 50 ng/mL or poorly differentiated tumor Those with life expectancy of less than 10 years or have non-reversible comorbidities undergo watchful waiting

42. Management of locally advanced disease Locally advanced disease and no regional nodal disease (N0) is managed like localized high risk (multimodal therapy) Those treated with radiotherapy with ≥ 2 high-risk factors (cT3-4 , PSA ≥ 40 ng/mL or Gleason ≥ 8) are given abiraterone for 2 years in addition to long term ADT For nodal positive (N1 disease) radiotherapy is given to the prostate and pelvis in combination long term ADT and abiraterone for 2 years

43. Adjuvant treatment for pN0 and pN1 after radical prostatectomy pN0 in the intermediate risk group (ISUP 2 and 3) with no positive surgical margins requires no adjuvant therapy pN0 high risk (ISUP 4 and 5) and pT3 ± positive margins adjuvant radiotherapy is given pN1 after extended lymph node dissection any of the following options can be offered Observation if ≤ 2 nodes and a PSA < 0.1ng/mL Adjuvant ADT Adjuvant ADT with additional radiotherapy

44. Persistent PSA after Radical prostatectomy or Radiotherapy PSMA PET/CT scan is done to rule out residual disease or microscopic metastatic disease if is PSA > 0.2 ng/mL is after RP If no evidence of metastatic disease salvage radiotherapy and additional hormonal therapy is offered When PSA elevation recurs after curative radiotherapy a mpMRI scan is done to localize abnormal areas Abnormal areas in the prostate should be subjected to lesion targeted TRUS biopsies If the patient is fit for salvage curative therapy a PSMA PET/CT scan should be done before treatment is instituted

45. Management after biochemical recurrence Follow up after any radical treatment should be done by serum PSA and imaging if it will influence the management If there is 2 consecutive increase in PSA after RP salvage radiotherapy plus additional hormonal therapy should be given Salvage radiotherapy or radical prostatectomy following biochemical recurrence post radiotherapy should only be done in clinical trials Non metastatic (M0) biochemical recurrence after radiotherapy with a PSA doubling time of < 9 months should be treated with enzalutamide with or without ADT

46. Management of hormone sensitive metastatic prostate cancer Proven M1 disease is treated with combined systemic therapy Combined systemic therapy consists of ADT (medical or surgical) and life prolonging agents or radiotherapy Life prolonging agents include androgens biosynthesis inhibitors, newer generation antiandrogens and chemotherapeutic agents An androgen biosynthesis inhibitor abiraterone is given together with prednisolone The newer generation antiandrogens include drugs such as enzalutamide, darolutamide and apalutamide

47. Management of hormone sensitive metastatic prostate cancer Radiotherapy is only combined with ADT for low volume metastatic disease by CHAARTED criteria Symptomatic patients should receive the treatment immediately to palliate the symptoms and prevent potentially serious sequelae of advanced disease Serious sequelae of advanced disease are ureteral obstruction, spinal cord compression and pathological fracture

48. Management of hormone sensitive metastatic prostate cancer Patients with impending clinical complications starting ADT should be offered either medical ADT by luteinizing hormone releasing hormone (LHRH) antagonist or surgical ADT (bilateral orchiectomy) I mpending clinical complications are spinal cord compression and bladder outlet obstruction Those scheduled to receive LHRH agonist should be placed on a short term older generation androgen receptor blocker (bicalutamide) to prevent “flare up phenomena”

49. Castrate resistant prostate cancer Progression of prostate cancer in the presence of confirmed serum testosterone below castrate levels ( 50ng/dL ) Castrate resistant prostate cancer can be non metastatic or metastatic Non metastatic castrate resistant prostate cancer is treated with newer generation androgen receptor blockers (apalutamide, darolutamide or enzalutamide) Patients who develop metastatic prostate cancer should undergo somatic and/or germline molecular testing as well as mismatch repair deficiencies or microsatellite instabilities

50. Mechanism for castrate resistant prostate cancer Proposed theories Amplification of androgen receptors resulting in tumor cells responding to low levels of endogenous androgens Mutation in the androgen binding domain allowing non androgenic steroids and antiandrogens to activate the mutant androgen receptors Deletion or splicing of the androgen binding ligand rendering the androgen receptors to become independent of androgens Development of non androgen mediated pathways

51. Castrate resistant prostate cancer Metastatic castrate resistant prostate cancer is treated with life prolonging agents Selection of the drugs partly depends on the previous treatment of the hormone sensitive metastatic prostate cancer and usually follow the alphabetical order These drugs include; abiraterone, cabazitaxel , docetaxel, enzalutamide,177lutetium-PSMA-617-radioligand therapy, radium-223, sipuleucel -T Patients with DNA homologous recombination repair alterations are given olaparib , olaparib /abiraterone, niraparib/abiraterone, rucaparib, talazoparib /enzalutamide

52. Supportive care for mCRPC Castrate resistant prostate cancer with skeletal metastasis are given bone protective agents to protect osseous complications Patients with low serum calcium are given calcium supplement (1000 mg/day) with vitamin D (800 u/day) together with bisphosphonates The most common bisphosphonate used is Zoledronic acid 4 mg IV 4 weekly for several months Painful bony metastasis are treated with adequate analgesia and radiotherapy Spinal cord compression is treated with immediate high dose corticosteroids followed up with surgery or radiotherapy

53. Spinal cord compression Patients with suspected spinal cord compress should immediately undergo MRI scan of the spine to exclude significant epidural disease The first therapeutic intervention for such patients include the administration of high doses of IV glucocorticoids Patients are often given IV loading dose of Dexamethasone 10mg followed by 4 to 10mg IV 6 hourly On improvement of symptoms steroid dose may tapered over 2 to 3 weeks period Radiotherapy with or without surgery is the mainstay treatment

54. References Lous R. Kavoussi , Andrew C. Novick, Alan W. Partin, Craig A. Peters, CAMPBELL-WALSH Urology , 12 th Edition, Chapters 148 to 162, Elsevier Saunders, USA. European Association of Urology, 2024 updated guidelines, limited edition.