1. MANAGEMENT OF PROSTATIC CANCER Gelawdiyos GSR 3

2. Outline Introduction Epidemiology Etiology and Risk factors Path physiology TNM Staging Work up and screening Management

4. Introduction Second most common cancer in men worldwide. Estimated 900,000 cases and 258,000 deaths in 2008. Clinical behavior ranges from a microscopic, well- differentiated tumor to an aggressive cancer with high likelihood of invasion and metastasis. Account about 15% of male cancers in developed countries compared to 4% of male cancers in undeveloped countries.

5. Epidemiology In the US, the incidence dramatically rose in the early 1990s concomitant with the increasing utilization of PSA testing. Genetic causes responsible in 5 – 10% and the rest is sporadic. Hereditary PCa usually have an onset 6-7 years prior to spontaneous cases. Only 16% of patient who was diagnosed to have prostatic ca ultimately die of it. Mortality rate from prostate ca declined significantly ( 2.5% per year. )

6. Etiology Exact causes of prostate cancer initiation and progression are not yet known. But both genetics and environment play a role in the origin and evolution of this disease. Genetic factors:- plays role in tumor initiation Environmental factor :- contributes in tumor progression ( latent form to clinical form)

7. Risk factors 1.Genetics If one first-line relative has PCa risk is at least doubled. If two or more first-line relatives are affected, the risk increases by 5-11-fold. Inter racial difference. 2. Age Strongest relationships between age and any human malignancy Clinically diagnosed rarely occurs before the age of 40, but the incidence rises rapidly thereafter The median age of clinical diagnosis is 68 Yrs. > 65% diagnosed between 55 and 74 yr. <10% clinical Dx in men under 55

10. 3.Race Asian countries have the lowest incidence. Afro-american has highest incidence and early age of onset of Pca. 4. Family studies Men with1st degree relative with prostatic CA has 2x risk. Men with 2 or 3 1 st degree relative with prostatic CA has 5-10x risk respectively

12. 5.Diet Diets that increase Risk High fat intake (polyunsaturated fats) - meats, diary product Zinc rich diets Calcium rich diets Diets that decrease Risk Vegetables :- like - lycopene ( anti-oxidant) rich – tomato based - Cauliflower Soy intake (Phytoestrogens) (flavones, isoflavones, lignans) - estrogen like activity - soya beans & legumes Vit.E and Folic acid coffee. Vitamin D rich diets

13. 6.Obesity Source of cytokines ( interleukins, transforming growth factor [TGF]-β) which a marker for cellular oxidative stress 7. Sexual activity and STD Expose prostate to infectious angent which increase the risk Increased safe sexual activity protective against prostatic cancer

14. 8.Asprin and NSAIDS 9.Hormones- higher concentration of testosterone & IGF-1---> Risk factors. 10.Folic acid ??? 11.Smoking 12.Vasectomy ???

15. Precursor prostatic cancer Prostatic intraepithelial neoplasia (PIN) Consist of Architecturally benign prostatic acini or ducts lined by cytological atypical cell. Retain basal cell Depending how close resemble true prostatic caner can be - High grade PIN ----80% ass with invasive ca - Low grade PIN ----20% ass with invasive ca

17. Prostatic Adenocarcinoma A rise from the acini of prostatic ducts >95% of prostate ca  Other rare histo-pathologic variants. (5% of patients) Urothelial ca (Transitional cell cancer) Mucinous carcinoma Endometrioid cancer (prostatic ductal carcinoma) Squamous cell carcinoma Basal cell carcinoma Adenoid cystic carcinoma (basaloid) Neuroendocrine cancer

18. Location  70% Peripheral zone ( T2 & >85% T1c) - PZ cancers are more aggressive. - Tend to invade the periprostatic tissue.  20% transitional zone - TZ prostate cancers are relatively nonaggressive  10% arise from central zone Site - >85 % multifocal - may appear to be unilateral on DRE.

19.  Volume - Size of the prostate ca correlate with the stage - Extraprostatic extension is uncommon tumor<0.4cm3 - LN metastasis and seminal vesicle invasion uncommon tumor< 4cm3  Grade -Based on the glandular pattern of the tumor as identified at relatively low magnification - score range from 2 to 10 - Both the primary ( predominant) and secondary( second most prevalent) archtecture identified and assigned from 1 to5.

20.  Score < or =4  well differentiated.  Score 5 – 7  Moderately differentiated.  Score > or = 8  poorly differentiated

22. Disease spread 1.Local invasion. Causes BOO, ureteral obstruction, rectal invasion (uncommon). 2. Lymphatic spread  usu. Obturator LN followed by iliac, pre-sacral & para-ortic LNs. 3.Distant spread  Axial skeleton is the most common site, particularly the lumbar spine.  Other bony sites are proximal femur, pelvis, thoracic spine, ribs, sternum & skull.  Bony lesions are typically osteoblastic,are sclerotic on x-ray.  Visceral spread tends to occur late can involve lungs, liver & adrenals

23. Clinical manifestations Early state (organ confined) Up to 50% of new prostate cancers are identified by PSA testing before the pt become symptomatic. By the time the pt develops sms from the tumor, 80% will have locally advanced or metastatic disease. The most common presenting picture are lower urinary tract SMS. Locally advanced Obstructive voiding symptoms,hesitancy, intermittent urinary stream,decreased force of stream,hematuria,hematospermia Advanced (spread to the regional pelvic lymph nodes) Edema of the lower extremities Pelvic and perineal discomfort Distant metastasis Bone metastasis  pain or pathological #.  Anemia. -Sxs of spinal cord compression ( par aesthesia, limb weakness, urinary & fecal incontinence

24. Screening for prostatic ca  The ACS and AUA recommend to offer the option of testing for early detection of prostate cancer to all men who are at least 50 years old (or younger if at higher risk).  PSA screening with DRE – Yearly after age 50 w/ 10 year life expectancy – May start at 45 w/ close relative w/ prostate cancer <65. – May start at 40 for multiple close relatives w/ prostate cancer <65 or Afro-american.

25. PROSTATE SPECIFIC ANTIGEN (PSA) Glycoprotein produced by prostate epithelial cells. Elevated in men with prostate cancer - Production is increased - Tissue barriers disrupted Studies have estimated that PSA elevations can precede clinical disease by 5 to 10 years or even longer.  B/n 4-10ng/ml  20 to 30% risk of cancer.  B/n 10-20ng/ml  the risk is 50 to 75%.  PSA > 20ng/ml  the risk rises to 90%. To improve the diagnostic performance of PSA when levels are less than 10.0 ng/Ml.

26. PSA velocity  >0.75ng/ml/yr  >90% specifity. PSA density  >or= 0.15. Free to complex PSA ratio >90% specific. - Free PSA is high in BPH, while PSA bound to alpha-1-antichemotypsin is high in prost.ca

27. DIGITAL RECTAL EXAMINATION  An irregular firm prostate,asymmetry or nodule is typical.  50% of suspicious lesion on DRE are actually represent cancer on prostate biopsy.  Prostate biopsy is recommended for a men who have DRE abnormalities regardless PSA level.  Up to 25% of men with cancer have PSA <4 ng/ml  85 % of cancers arise peripherally where they can be detected with a finger examination

28. Staging Goals 1.To provide prognosis. 2. To rationally select therapy based on the predicted extent of the disease.  Pathological staging is the most reliable means of predicting out come of definitive treatment.  Clinical staging- refers to assessment of the extent of disease determined by DRE, serum tumor markers, tumor grading & imaging modalities.

29. Staging Modalities 1.DRE  sensitivity of 52% & specifity of 81% for prediction of organ confined disease. 2.Serum tumor markers. A. Serum prostatic acid phosphatase (PAP) -Not prostate specific. - Abnormal value suggest a high likelihood of extraprostatic disease ( >80% ). B. PSA  Concentration of PSA directly related to the volume of cancer present

30. General guide lines  80% of men with PSA value <4ng/ml have pathologically organ confined disease.  PSA 4-10ng/ml  2/3 have organ confined ca  PSA level >10ng/ml  >50% of men have disease beyond the prostate.  PSA >20ng/ml  ~20% have pelvic LN involvement.  PSA >50ng/ml  75% have pelvic LN involvement.

31. 3. Histologic grade  In general high biopsy grade have worse pathologic staging. 4. Imaging  Staging CT scan & bone scan is recommended to a men with PSA >10ng/ml,Hign grade histology (GS>or=7) or physical finding suggesting T3 dis.  CT scan can evaluate extension in to bladder and LN.  Bone scan  superior to conventional radiography may reveal in up to 25% of bone metastasis of pts with normal radiography. 4.Pelvic LN dissection  provides the most accurate staging information

32. Work up 1.Biochemical test  RFT  deranged in bilateral ureteric obstruct.  CBC:- pancytopnea  extensive bone marrow infiltration.  Increased serum alkaline phosphatase  presence of bone metastasis. 2. TRUS & prostate biopsy.  Sextan prostate biopsy  Extended core biopsy techniques  CXR, PT & PTT, ECG.

33. Indication  Abnormal PR finding  Elevated PSA Contra indication  Coagulopathy  Painful anorecatal condition  Acute prostatitis  Severe immunosuppression

35. TNM Staging

36. Stage I or Stage A Prostate Cancer Stage I cancer is found only in the prostate and usually grows slowly Stage I cancer is found only in the prostate and usually grows slowly

37. Stage II or Stage B Prostate Cancer Stage II cancer has not spread beyond the prostate gland, but involves more than one part of the prostate, and may tend to grow more quickly Stage II cancer has not spread beyond the prostate gland, but involves more than one part of the prostate, and may tend to grow more quickly

38. Stage III or Stage C Prostate Cancer Stage III cancer has spread beyond the outer layer of the prostate into nearby tissues or to the seminal vesicles, the glands that help produce semen Stage III cancer has spread beyond the outer layer of the prostate into nearby tissues or to the seminal vesicles, the glands that help produce semen

39. Stage IV or Stage D Prostate Cancer Stage IV cancer has spread to other areas of the body such as the bladder, rectum, bone, liver, lungs, or lymph nodes Stage IV cancer has spread to other areas of the body such as the bladder, rectum, bone, liver, lungs, or lymph nodes

40. Management Depends on the stage of the disease at presentation, pts age, their life expectations & co morbidities. Three standard options. 1.Radical prostatectomy. 2. Radiation therapy. 3.conservative management - active surviellance - Watchful waiting -Hormonal therapy reserved for pts with locally advanced or metastatic prostate ca or as a supplementation.

41. 1.Clinically localized prostate ca (T1/T2N0M0) The optimal form of therapy remain a subject of controversy. Treatment option ranges from observation to Radical treatment. Factors should be considered in to the decision for section therapy. 1. Life expectancy of the pts. (age & comobidies) 2.The biological charactestics of the tumor. 3. The preference of the pt.

42.  Radical treatment in general offered to a men with life expectancy 10 or more yrs. Non-surgical treatment 1. Watchful waiting  A program of serial PSA monitoring & DRE.  Often preferred for elderly asymptomatic men with small,well diffentiated tumor, localized or those who have significant life-limiting comobidies.  Intervention when patient develop metastasis which require palliative treatment.

43. 2.Active surveillance  No treatment at all for patients older than 70 years, while in younger patients, it might mean a possible treatment delayed for years.  Follow up include semiannual PSA, DRE and Annual biopsy. Intervention when - Gleason score >= 4 or 5 - > 2 core biopsy positive  Radical managment

44. 3. Androgen ablation.  Used for a pt unwilling to undergo potentially curative treatment.  Given in the form of LHRH agonist, LHRH antagonist, oral anti-androgen. 4.Radical Radiotherapy -Cure rate is comparable to RP at least for the 1 st 5 year.

45. A. External beam radiotherapy.  Used with the curative intent for pts with clinically localized ca.  When it is combined with androgen ablation  improve disease specific survival & increase time to recurrence. Complications -cystitis (5%) -Incontinence (7-10%) -Proctitis (2- 39%) -Enteritis -Impotence (40 to 50%)

47. B. Interstitial radiotherapy or Brachytherapy -Implantation of radioactive seeds directly in to the prostate under U/S control. -Used to a men with small, well differentiated tumor. - Can be used as a salvage therapy for pts in whom external beam radiation therapy has failed. Advantages –convenience. -Negligible radiation exposure. -It appears to be equivalent to other treatment modalities. -Has inferior outcome for higher GS or high pretreatment serum PSA level.

48. Complications -Rectal injury (5-10%). -Bladder damage (10-20%). -Impotence (50-60%). -Haematuria (5-10%). -Urinary incontinence ( upto 30%). Outcome 1.Low risk (T1c,OR T2a,PSA <or=10ng/ml, Biopsy GS <or=6)  Have 80-90% 5 yrs PSA-failure free survival rate. 2.Intermidiate risk (T2b,PSAb/n 10-20ng/ml,biopsy GS 7)  Have 50% 5 yrs PSA failure-free survival. 3.High risk ( T3c,PSA>20ng/ml,biopsy GS>or=8).  Have 25to30% 5 yr PSA failure-free Survival rate.

49. Surgical 4. Radical Prostatectomy -Involves removal of prostate, SV, & obturator & pelvic LNs if necessary. -Can be performed via a retro-pubic or perineal approach or laparascopically. Pt selection criteria for RP. a. PT age < 75 yr. b. Few co morbidities with life expectancy>10yr. c. Gleason score <or= 7. d. Serum PSA level < 20ng/ml.

52. A 15 yr progression free survival rates without evidence of metastastatic disease have been reported 80-85% for selected men with organ confined disease. Complications. -Mortality ( <o.3%). -Impotence ( <50%). -Long term incontinence ( <5% ). -Pulmonary embolism ( <1% ). -Urethral stricture ( < 5% ). - UTI - Lymphocele

53. 2. Locally advanced prostate Ca (T3NxMo )  12 to 28% of newly diagnosed pts have clinical stage T3.  Characterized by palpable in duration, that extends in to lateral sulci or cephaled in to the SV.  Evaluation of the local extent of the disease is typically accomplished with combined DRE, CT scan & TRUS.  Optimal treatment  controversial.  Surgery &/or radiotherapy are generally considered for local control.  Control of distant disease requires hormone therapy.

54. A. Watchful waiting -An option only in highly selected pts with life expectancy of < 5yr. B. Hormone therapy - May be used alone or as an adjuvant therapy combined with RP or radical radiotherapy. - LHRH agonist, anti-androgens & orchidectomy are the commonest form.

55. C. Surgery. 1. Conservative surgery TURP –can provide local control of the tumor & palliation for obstructive SMS. 2. Radical prostatectomy. -Not widely accepted. -T3a have favorable long term out come. Pt selection - PSA <10ng/ml & low to moderate GS  have 60 to 70% 5 yr PSA failure- free survival rates.

56. 3.Adjuvant therapy. -Hormone or radiotherapy may improve the out come after RP. - Post operative radiation therapy usually given to a men with poor risk factors ( T3-4) GS >or= 7 & positive margins of resection. It decreases local recurrence but has no survival benefits. -Adjuvant hormone therapy is recommended for a persistently detectable serum PSA level following prostatectomy.

57. D. Radiotherapy. - a usual Rx for majority. -Most often given as EBRT. -Clinical results with EBRT.10 yr overall survival  33-45%..15 yr overall survival  18-30%.. 10 yr biochemical disease free survival  10-30%. -Neoadjuvant hormone therapy is currently as a standard adjuvant to EBRT for locally advanced prostate ca. Brachytherapy -Usually combined with EBRT. -Enhance local control.

58. 3. Metastatic prostate cancer. -Once the prostate ca has metastasized the out come is poor, with 90% mortality in 5 yrs of time. Hormone treatment -The treatment of choice. -20 – 30% of tumor  resistant. -Medical & surgical androgen ablation alleviates SMS in 80-90% of pts & prolong survival. -Relapse usually occurs after an average interval of 18 to 24 months.

59. Methods of androgen deprivation. 1. Bilateral Orchiectomy 2. Estrogen therapy. 3. LHRH agonist. 4. LHRH antagonist. 5. Antiandrogen therapy. ~90% of circulating testosterone is removed by orchiectomy, decrease symptomatic bone pain.

60. 2. Palliation. - NSAIDS, Opiates -Localized radiotherapy to the affected region provides good pain control. Follow up. -Not standardized. 1. Watch full waiting & androgen ablation. -A DRE & PSA test  every 3-12 months. -Bone scan  Yearly once serum PSA > 40ng/ml.

61. Follow up cont. 2. RP - PSA testing  every 3-4 months for the 1 st 2 yrs, every 6 months for the 3 rd & 4 th yr yearly thereafter. 3. EBRT. DRE & PSA testing every 3-6 months for 5 yrs  annually. 4.Brachytherapy. -PSA testing  every 3-6 month for 1 yr then annually. Biopsy at 18 -24 month.

62. Biochemical recurrence. Considered to be occurred following 1. RP- if PSA >or= 0.2ng/ml. 2. RT – 2-3 consecutive rise in PSA. -When PSA level begins doubling every 10-12 month or reaches 20ng/ml  Imaging studies recommended. -Bone scan -CXR -CT scan of the abdomen & pelvis. - TRUS guided rebiopsy of prostate or prostatic fossa. -Pistron emision tomography.

63. Salvage therapy Considered for pts who have PSA failure following RP & have no evidence metastasis. Treatment option -Watch full waiting -Radiotherapy -Hormone ablation  Pts who have PSA failure following RT options –Watchful waiting, prostatectomy -Cytoprostatectomy -hormonal ablation.

64. References Campbell’s text book of urology, 10 th edition Uptodate 19.3 Oxford American Hand of urology EUA guideline on Prostate cancer Internet

65. Thank you