CA Prostate

carcinoma prostate from anatomy to management

1. Prostate Cancer: Anatomy to Management Dr. Ayush Garg

2. Anatomy Of Prostate The prostate is a walnut-sized gland located in front of the rectum and below the bladder. It surrounds the urethra, the tube-like channel that carries urine and semen through the penis. The primary function of the prostate is to produce seminal fluid, the liquid in semen that protects, supports, and helps transport sperm .

3. Base of the Prostate The base is directed upward near the inferior surface of the bladder. The greater part of this surface is directly continuous with the bladder wall. Apex of the Prostate The apex is directed downward and is in contact with the superior fascia of the urogenital diaphragm. Anatomy Of Prostate

4. Anatomy Of Prostate Blood supply Inferior vesical artery Derived from the internal iliac artery Supplies blood to the base of the bladder and prostate Capsular branches of the inferior vesical artery Help identify the pelvic plexus Nerve supply Neurovascular bundle Lies on either side of the prostate on the rectum Derived from the pelvic plexus , arising from the S2-4 and T10-12 nerve roots Important for erectile function.

5. Prostatic Zonal Anatomy There are four zones of the prostate : the peripheral zone (PZ) , transition zone (TZ) , Central zone , and anter i or fibromuscular stroma zone .

6. Peripheral zone (PZ) 70% of cancers Transitional zone (TZ) 20% TZ prostate cancers are relatively nonaggressive PZ cancers are more aggressive Tend to invade the peri - prostatic tissues.

7. Lymphatic Drainage

8. Regional Lymph Nodes Pelvic Hypogastric Obturator Iliac (internal, external) Sacral (lateral, presacral , promontory [ Gerota's ])

9. Metastatic Lymph Nodes Distant lymph nodes lie outside the confines of the true pelvis. The distant lymph nodes include the following: Aortic ( paraaortic lumbar) Common iliac Inguinal , deep Superficial inguinal (femoral) Supraclavicular Cervical Scalene Retroperitoneal

10. Epidemiology Second leading cause of cancer death in men from western countries It is one of the 10 leading cancer sites in males in India, accounting for about 4 % all male cancers Age-adjusted annual incidence 176 per 100,000 in USA, whereas only 7.1 in Mumbai and 4.3 in Bangalore (NCRP 1990-96)

11. Etiology Family history: 2-3 fold increased risk in men with a first degree relative. Hereditary association : Early onset of disease and a Mendelian autosomal dominant inheritance– accounting for <10% of all cases but 40% in younger men in <55 years. Racial Factors : Striking differences in incidence and mortality between the Black and White population, more common in blacks. Environmental Factors: also responsible for ethnic differences, as Asians migrating to USA have higher incidence of prostate cancer.

12. Etiology Diet : one of the most important modifiable risk factors -- high fat intake increases risk whereas diets rich in carotenoids (tomato based products containing lycopene) and vitamin-E are protective. No association with cigarette smoking, alcohol use, height and weight and blood group. No data regarding viral origin. No convincing evidence that Vasectomy increases risk of prostate cancer

13. Pathology Adenocarcinoma 95% of prostate cancers Developing in the acini of prostatic ducts Rare histopathologic types of prostate carcinoma Occur in approximately 5% of patients Include Small cell carcinoma Mucinous carcinoma Endometrioid cancer (prostatic ductal carcinoma) Transitional cell cancer Squamous cell carcinoma Basal cell carcinoma Adenoid cystic carcinoma ( basaloid ) Signet-ring cell carcinoma Neuroendocrine cancer

14. CLINICAL MANIFESTATIONS EARLY STAGE Asymptomatic Cancer is in the peripheral zone LOCALLY ADVANCED DISEASE Obstructive / irritative voiding Hesitancy Intermittent urinary stream Decreased force of stream --- May have growth into the urethra or bladder neck Retention of urine Hematuria Hematospermia Renal failure Pelvic pain ADVANCED DISEASE (spread to the regional pelvic lymph nodes) Edema of the lower extremities Pelvic and perineal discomfort METASTATIC DISEASE Bone pain Spinal cord compression symptoms Paraperesis

15. Hematuria - prostatic urethra/ trigone involvement Hematospermia Extra prostatic spread- often asymptomatic/ extensive dis. Rectal involvement- Hematochezia Constipation Intermittent diarrhoea Abdomino -pelvic pain Renal impairment due to prolonged bladder outlet obstruction. Fluid retention/ electrolyte imbalance

16. Involvement of neurovascular bundles/ GUD: ------- Impotence/ pelvic pain/ priapism Advanced disease- metastatic symptoms Bony- pain / pathological fracture/ Spinal tenderness Spinal cord compression- neurological deficits/ sensory-motor changes/ bladder-bowel dysfunction Pelvic / Para aortic LAP- edema of abdominal wall, genitalia or lower extremities/ mass abdomen Adrenal/ lung/ skin metastasis. PNS- SIADH/ Cushing syndrome.

17. STAGING OF PROSTATE CANCER

18. DIAGNOSTIC WORK-UP Laboratory Complete blood cell count, blood biochemistry Serum PSA (total, free, percentage free) Plasma acid phosphatases (prostatic/total) Radiographic imaging Transrectal ultrasonography (for biopsy guidance) Biopsy/Needle biopsy of prostate ( transrectal , transperineal ) Chest radiograph (high risk for metastatic disease) Computed tomography of pelvis. Radioisotope bone scan Magnetic resonance imaging. PET CT Scan for metastasis in high risk cases

19. Diagnosis • Signs and symptoms of Prostatism • Abnormal DRE : although correlates poorly with the volume and extent of cancer, an integral part of the algorithm . • Serum PSA : usually > 4 ng /ml With increasing PSA level, chance of getting cancer increases, but less likely to be organ confined. • TRUS guided Biopsy : 1 ) to establish the diagnosis. 2) to report extent and grade of cancer in each core. 3) to document presence of PNI or ECE.

20. The Number of Cores Removed In 1990s 6 core biopsy was done but now 12 core biopsy is done. Many different theories exist as to the “best” way to “sample” the prostate so as to find any cancer that may be present. There are no “absolute” prostate biopsy guidelines . Cores from all major regions of the prostate so as to ensure complete “geographic” coverage is done. Cores from any region of the prostate that felt suspicious under DRE or TRUS is done. Biopsy sites included the 1. midlobe parasagittal plane at the apex, 2. the midgland , and 3. the base bilaterally.

21. LABORATORY INVESTIGATIONS PROSTATE SPECIFIC ANTIGEN Serine protease glycoprotein secreted by prostatic epithelium Carcinoma specific Normal : 0.4 - 4 ng/ml (upper limit 2.6 ng/ml) t 1/2 : 2.2― 3.2 ±0.1 days Mild elevation 4 ― 10 ng/ml Significant elevation >10 ng/ml Sensitivity ― 85% Specificity – 65-70% Estimated rate of cancer detection by PSA screening ― 1.8-3.3% Carcinoma with normal PSA ― 25%

22. Age specific PSA : Age PSA 40-50 0-2.5 60-70 0-4.5 70-80 0-6.5 Pretreatment serum PSA is also predictive of EPE and SVI : PSA Rate of organ-confined disease 4 -10 ng /ml 53% - 70% 10 -20 ng /ml 31% - 56% Roach’s Probability of ECE, SVI and LNI : ECE+ = 3/2×PSA +(GS-3)×10 SVI+ = PSA +(GS-6)×10 LNI+ = 2/3×PSA +(GS-6)×10

23. Digital Rectal Examination Cornerstone of the physical examination/ instrumental in staging Sim’s lateral position. Organ palpation: Craniocaudal and transverse dimension Consistency / Mobility Any firm/ elevated area and its size. Typical finding ca prostate - Hard, nodular, asymmetrical, may or may not be raised above the surface of gland and is surrounded by compressible prostatic tissue. Prostatic induration - BHP nodule/ calculi/ infection/ granulomatous prostatitis / infarction Specificity- 50% and Sensitivity- 70% Only 25-50% of men with an abnormal DRE have cancer. DRE + PSA specificity 87%

24. Prostate Anatomy on DRE

25. TRANRECTAL ULTRASONOGRAPHY( trus ) TRUS of the prostate, first described by Wantanabe (1968) TRUS-guided systematic sextant biopsy protocol by Hodge Normal adult prostate : Symmetric, triangular, relatively homogenous structure with an echogenic capsule The mature average prostate is between 20 and 25 g and remains relatively constant until about age 50, when the gland enlarges in many men ( Griffiths, 1996 ) The paired seminal vesicles are positioned posteriorly at the base of the prostate. They have a smooth, saccular appearance and should be symmetrical. Normal SV measures 4.5 to 5.5 cm(l) and 2 cm (w)

26. Extraprostatic extension Sensitivity-66% Specificity- 46% Accuracy- 58% Seminal vesicle invasion Echogenic abnormalities Ant. displacement and enlargement of SV

27. TRUS-directed prostate needle biopsy remains the gold standard for diagnosis of prostate cancer Guided biopsy of the prostate Recommendation: TRUS guided Bx in patients with PSA> 4 ng/ml To establish the diagnosis To report extent and grade of each core To document presence of Pelvic LN involvement and ECE Staging of clinically localized prostate cancer Guidance during the seed/interstitial brachytherapy Monitoring prostate cryotherapy Evaluation and aspiration of prostate abscess Monitoring the response to prostate cancer treatment

28. Gleason’s Score Donald F. Gleason in 1966 created a unique grading system for prostatic carcinoma based solely on the architectural pattern of the tumor .

29. Gleason’s Score Prostate cancer has a pronounced morphological heterogeneity and usually more than one histological pattern is present. The primary and secondary pattern, i.e. the most prevalent and the second most prevalent pattern are added to obtain a Gleason score or sum. It is recommended that the primary and secondary pattern as well as the score be reported, e.g. Gleason score 3+4=7. If the tumour only has one pattern, Gleason score is obtained by doubling that pattern, e.g. Gleason score 3+3=6.

30. Grades Primary grade - assigned to the dominant pattern of the tumor (has to be greater than 50% of the total pattern seen). Secondary grade - assigned to the next-most frequent pattern (has to be less than 50%, but at least 5%, of the pattern of the total cancer observed) Gleason Score= Predominant pattern (1-5) + Secondary pattern (1-5) Best Score=2, Worst Score=10

31. IMAGING CXR Pulmonary metastasis Miliary pattern Axial skeletal survey : Specific sites of bony pain Osteoblastic secondaries USG abdomen-pelvis: hydroureteronephrosis large post void residual urine volume retroperitoneal lymphadenopathy Liver mets .

32. CT SCAN Primary role Size determination of the gland Assess pelvic LN metastasis Treatment planning in RT Extra Prostatic Extension: Loss of periprostatic fat planes Bladder base deformity Obliteration of the normal angle b/w the SV and post. aspect of UB LN involvement Abnormality in size Sensitivity 25% Reserved for patients with higher PSA values (>20-25 ng/ml) CT guided FNAC

33. Limitation of CT Lacks the soft tissue resolution needed to detect intraprotatic anatomic changes due to primary tumor , capsular extension or SVI because the neoplasm usually has the same attenuation as the normal prostate gland Can't detect microscopic disease False Positive- Artifact of Bx and plane b/w SV and UB base may be obscured by rectal distension

34. MRI Superior to CT in defining prostate apex, NVB and anterior rectal wall Better delineation of periprostatic fat involvement T1w- provides high contrast b/w water density structures i.e. Prostate, SV and fat, NVB, perivesical tissue and LNs T2w fast spine echo- zonal anatomy, architecture of SV Ca Prostate: A focal, peripheral region of decreased signal intensity surrounded by a normal(high intensity) peripheral zone BHP: centrally located nodules of similar signal Primary staging sensitivity- 69% Endorectal surface coil MRI- accuracy of 54-72% staging the primary and detects SVI and ECE

35. Indications: High likelihood of capsular invasion and LN metastasis Abnormal DRE PSA>20 Poorly differentiated ca Sensitivity to locate gland tumor- 79% and specificity- 55% LN detection- Low sensitivity but high specificity

36. MRSI ( Magnetic Resonance Spectroscopic Imaging ) Improved diagnostic accuracy of MRI both in localizing and staging and risk-stratifying patients Specificity for tumor location (MRI + MRSI) ~ 91%. Accurate localization of prostate tumors and improved guided biopsy Combined MRI/MRSI enhances the assessment of both ECE and SVI and capsular breech Predict tumor aggressiveness Distinguishing b/w tumor and post biopsy hemorrhage Detect residual cancer following t/t and follow-up Development of more focused therapy

37. 99 Tc BONE SCAN Clinically apparent metastatic disease limited to bone in 80-85% of patients of metastatic ca prostate Osteoblastic secondaries MC sites of metastasis Vertebral column- 74% Ribs- 70% Pelvis- 60% Femora- 44% Shoulder girdle-41% Indications: Pretherapy Early stage disease-T 1 -T 2 with PSA > 20 ng / ml GS≥ 8 Bony pain T 3 -T 4 –Symptomatic patients High grade tumor Base line: Elderly, patients with h/o arthritis, to document degenerative changes that may later be interpreted as metastatic osseous disease and to assess t/t effectiveness

38. What is a Prostate-Specific Membrane Antigen (PSMA) study? PSMA studies are performed on newly diagnosed prostate cancer patients to determine if the disease has spread to pelvic lymph nodes. The study is also performed on patients who have had their prostate gland removed and have an increase in prostate-specific antigen (PSA) blood levels . PSMA is a membrane glycoprotein which is overexpressed manifold on prostate cancers, and the expression increases with Tumor Aggressiveness, Androgen-independence, Metastatic Disease, Disease recurrence

39. Ga-68 PSMA PET/CT Imaging identifies tumor cells expressing PSMA antigen with excellent sensitivity & specificity, thereby detecting lesions remaining unidentified by conventional methods. The study involves a special molecule called a monoclonal antibody developed in a laboratory and designed to bind to the prostate-specific membrane antigen on cancer cells. This antibody is paired with a radioactive material called Gadolinium 68 that can be detected by a gamma camera. When injected into the patient’s bloodstream, the radioactive antibody travels and attaches to cancer cells. The gamma camera then produces three-dimensional images of the tumor and its location inside the body .

40. Advantages / Indications: PET Imaging with 68Ga-PSMA ligand can present lesions suspicious for prostate cancer with excellent contrast and a high detection rate even when the level of prostate specific antigen is low PSMA expression allows the identification of benign and malignant prostatic epithelium and may be a potentially valuable marker in the treatment of patients with prostate cancer 68Ga-PSMA PET has promising potential for restaging in recurrence/ biochemical failure after definitive treatment of prostate cancer PSMA PET could be used as a marker of patient response to anti-androgen drugs

41. This 73-year-old man was recently diagnosed with prostate cancer and has an elevated PSA. PET/CT shows the intense activity in the prostate cancer (arrow) and the spread to the left pelvic bone (b).

42. T reatment Depends on stage, patient's age and GC EARLY LOCALLY ADVANCED METASTATIC 3 risk group Stage Initial PSA GS LOW RISK T 1 –T 2a <10 ng/ml ≤ 6 INTERMEDIATE RISK Bulky T 2b 10- 20 7 HIGH RISK ≥ T 2c >20 8-10 ( D'Amico et al ) Localized disease Observation Radical radiotherapy Radical prostatectomy Cryoablation Locally advanced disease Radical radiotherapy Hormonal therapy Metastatic disease Palliative RT Hormonal therapy RISK STRATIFICATION STAGE PSA GLEASONS SCORE

43. SURGERY

44. RADICAL PROSTATECTOMY Described by young et al. (1905) & popularized by Jewett Procedure: Complete removal of prostate ,surrounding capsule, seminal vesicle,ampulla, vas deferens . Approaches Retropubic Transperineal Laproscopic 1.pure 2. robot assisted-(da vinci robotic arm)- less blood loss 10 fold magnification three dimensional visualization. Watertight anastomosis eases early removal of catheter. o Selection: clinically localized prostate ca (cT1- cT3a,N0/Nx,M0/Mx) <60 yrs Good GC Life expectancy >10yrs No life threatening ancillary disease E V O L U T I O N

45. WATCHFUL WAITING RADICAL PRO S T A T E C T OMY RR 348 (AS) 347 (RP) 0.56 (CI- 0.3 6 - 0.88) DEATH 50 30 0.6 (CI-0.42- 0.86) METS LOWER RISK OF M E T AS T A S IS Cumulative probability of developing metastatic disease 10 yrs after diagnosis 25% in conservatively managed patients . Cancer specific mortality 25% in the WW patients. Absolute & statistically significant increase in OS at 10 yrs for patients in surgery arm. SCANDINAVIAN TRIAL 695 men with clinically localized cancer prostate RP vs. watchful waiting with systematic treatment deferred until disease progresses.

46. Patient selection for pelvic lymph node dissection: Definitely men with pelvic node involvement fare poorly. So controversy persists about PND. Low risk disease - Pelvic node involvement chance < 5 %. LN dissection : excision of fibrofatty tissue & lymphatic tissue between bifurcation of common iliac artery superiorly to the femoral canal inferiorly and to pelvic sidewall laterally. Posteriorly to obturator nv. Extended LN: conventional LN with posteriorly obturator vessels and iliac vein. Current practice : to restrict PLND at time of RP to men with a ≥ 2% risk of positive nodes according to a contemporary nomogram .

47. Radiotherapy

48. RADIOTHERAPY Adjuvant Radical Palliative Techniques: Conventional 3D CRT IMRT & IGRT Proton Therapy Brachytherapy

49. Adjuvant RT Indications: Immediate- after RP with positive Sx margins, SVI, poorly diff. ca (GS 8-10), LN mets Delayed- ↑PSA level with no e/o distant mets, clinically local recurrence and LN me ts

50. Localization, Immobilization, and Simulation ■ Patient preparation: full bladder and empty rectum minimizes dose to critical structures (bladder, small bowel, rectum). ■ Patient position: supine, with arms folded on the chest. ■ Immobilization: ■ Consider a body mold such as a vacuum-lock immobilization bag. ■ A knee bolster with the feet banded together provides a comfortable and reproducible position. ■ Simulation: CT scan from midabdomen to midfemur . ■ CT should include the L4-L5 intervertebral disk level superiorly to below the lesser trochanters inferiorly .

51. Conventonal For historical purposes, with conventional technique , pelvic irradiation is usually treated with a four-field box. The target volume usually includes the prostate, seminal vesicles, obturator, and proximal internal and external iliac nodal regions . Occasionally common iliac, para-aortic, and even perirectal nodes are included in the initial target. With CT planning , the prostate, seminal vesicles, rectum, small bowel, bladder , pelvic vessels, and penile bulb may be contoured to facilitate shielding of the rectum and small bowel.

52. Field size : Superior border-L 5 -S 1 Inferior border- 1.5-2 cm distal to junction of prostatic and membranous urethra (lower border of ischial tuberosity) Lateral border- 1.5-2 cm lateral to bony pelvis Common iliac LN treated by 18X15 cm field Corner blocks are usually placed at all four corners to limit dose to the small bowel and femoral heads.

53. Anterior margin-0.5 to 1 cm posterior to projected cortex of PS Posterior margin-S 2-3 interspace to include the upper presacral LNs

54. Boost field Superior border extends to the top of the acetabulum - 3-5 cm above pubis Anterior border-1.5 cm posterior to ant. margin of pubic symphysis Posterior border- 2 cm behind the rectal marker Inferior border- short of internal anal sphincter or caudal to ischial tuberosity Laterally to include 2/3 of the obturator foramen

55. SEQUELAE OF RT Conventional: Acute – 60% in 3 rd week of RT Rectal - discomfort, tenesmus, diarrhoea Urinary- frequency, urgency, nocturia Urinary incontinence (any 0–60%, severe 2–15%) Late – 6 months/ later Chronic diarrhoea , proctitis, rectal-anal stricture Bleeding PR- 3.3%, bowel obst./ perforation- 0.6% Fatal complication- 0.2% Rectal toxicity is propotional to volume of rectal wall exposed to high dose (any 2–100%, severe 0–20%) Erectile dysfunction (10–85 %)

56. Target Volumes CTV = entire prostate +/- seminal vesicles +/- LN. ■ Low-risk prostate cancer CTV = entire prostate only. ■ Intermediate-risk prostate cancer CTV = prostate + proximal 1 cm of the bilateral seminal vesicles. ■ High-risk prostate cancer CTV = prostate + proximal 2 cm of the bilateral seminal vesicles (consider entire seminal vesicles if grossly involved) +/- LN regions. ■ Definition of the PTV ■ PTV margin depends on the immobilization technique and the particular IGRT technology being used. ■ With CBCT IGRT, an 8 to 10 mm expansion is used, except posteriorly, where a 5 to 8 mm margin is used. The PTV expands into the rectum, whereas the CTV does not.

57. Representative pelvic lymph node clinical target volume (CTV) contours from RTOG consensus computed tomography. A , Common iliac and presacral CTV lymph node volumes (L5/S1). B , External, internal, and presacral CTV lymph node volumes (S1-S3). C , External and internal Iliac CTV lymph node volumes (below S3). D , End of external iliac CTV lymph node volumes (at top of femoral head, boney landmark for the inguinal ligament ). E , Obturator CTV lymph node volumes (above the top of the pubic symphysis).

58. Dose/ Fractionation Total prescription dose of 75.6 to 79.2 Gy in 1.8 to 2 Gy / fx for low risk cancers and intermediate or high risk cases doses upto 81 Gy provide improved PSA assessed disease control. ■ If treating LN prescribe initial 45 to 50.4 Gy /1.8 Gy / fx to the pelvis (lymph nodes + prostate + seminal vesicles). Grossly positive lymph nodes can be boosted to a higher dose. ● Boost the seminal vesicles to 54 to 66 Gy , pay attention to small bowel position and potential for toxicity, and boost the prostate alone to final prescription dose .

59. LANDMARK TRIALS RTOG 9413 (2003) Whole Pelvic RT followed by Prostate Boost versus Prostate Only RT 4 months of Neo Adjuvant Hormone Therapy + Concurrent Hormone Therapy or 4 months of Adjuvant Hormone Therapy Result Whole Pelvic RT + Neo Adjuvant Hormone arm had 59.6% of 4 years PSA relapse free survival better than other arms.

60. The delivery of radiotherapy has changed considerably since the 1980s. For example, the integration of various forms of IGRT for EBRT and brachytherapy, and delivery with IMRT for EBRT planning, have enabled accurate dose escalation to improve outcomes and reduce toxicity. Furthermore , radiobiological models have suggested that prostate cancer cells are more sensitive to doses delivered in larger fraction sizes than in smaller, more frequent doses; normal tissues experience less toxicity with such doses.

61. Target Volume Definition for EBRT: Post-Prostatectomy Definition of prostate bed CTV: ■ CTV = prostate bed +/- remnant seminal vesicles. ■ Contour the prostate bed inferiorly to below the urethrogram beak and continue to the top of the pubic symphysis. ■ Extend the contours laterally to the medial edge of the sacro-rectogenitopubic fascia bilaterally. Where this fascia is not visible one may alternately use the medial border of the obturator internus. ■ Anteriorly include the bladder up to the pubic symphysis with gradual reduction posteriorly and superiorly to the bladder for 1 to 2 cm above the pubic symphysis. ■ Include at least 1 cm of the posterior bladder in the CTV. Extend more superiorly for patients with pathological involvement of the prostate base or seminal vesicles.

62. ■ Include surgical clips around the prostate bed. Do not include hemostasis clips higher in the pelvis if the seminal vesicles are uninvolved. ■ Definition of the PTV. ■ PTV = 7 to 10 mm around the CTV. Posteriorly toward the rectum, the margin may be reduced to 5 mm. ■ Tighter margins may be used with more advanced IGRT and immobilization. Dose/Fractionation ■ Doses of 64.8 to 70.2 Gy in 1.8 to 2 Gy per fx are used postoperatively. ■ A distinction can be made between adjuvant (absence of detectable disease) and salvage (presence of detectable disease) as follows: ■ 64 to 66 Gy for adjuvant therapy

63. IMRT GTV adenocarcinoma of the prostate is not visualized well and therefore is not contoured separately. TARGET LOW RISK INTERMEDIATE RISK HIG RISK CTV1 PROSTAE +/- PROXIMAL SEMINAL V E SICL E S (74 G Y) PROSTATE +PROX. SEMINAL VESICLE(76-78GY) PROSTATE=GROSS ETRACAPSULAR DISEASE &PROX.SEMINL VESICAL(76- 78GY) CTV2 -- DISTAL SEMINAL VESICALS(56 GY) DISTAL SEMINAL VESICLES AND LN(56 GY)

64. Prostate Motion To see: Interfractional motion: Movement on daily basis. Intrafractional motion: Movement during treatment. Is the positional relationship between the prostate and bony anatomy static? Interfractional 3D displacement of prostate and bony anatomy were 5.6 &4.4 prior to localization,2.8 &4.4 mm After post localization system.---thus bony landmarks is not sufficient for accurate localization of the gland. Hence came the role of Fiducial Gold Seed markers with daily electronic portal imaging

65. Dose Escalation ■ A hypofractionated regimen of 70 Gy /2.5 Gy / fx may be considered. Other hypofractionated schedules include 70.2 Gy /2.7 Gy / fx , 62 Gy /3.1 Gy / fx (4 fx /week), or 51.6 Gy /4.3 Gy / fx .

66. Dose Escalation in CA Prostate Phase III randomized trial from MD Anderson Hospital (2008) Arms 8 years Biochemical Control PSA Relapse Free Survival I 70 Gy Conventional 63% 64% II 78 Gy Conventional + 3D Boost 88% 70% Kuban DA, Tucker SL, Dong L et al (2008) Long-term results of the MD Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 70:67 –74

67. RTOG 94-06 Dose escalation using 3D CRT 5 Sequential Dose Levels 5 years PSA Relapse free survival 68.4 Gy @ 1.8Gy/# 68% 73.8 Gy @ 1.8Gy/# 73% 79.2 Gy @ 1.8Gy/# 67% 74 Gy @ 2Gy/# 84% 78 Gy @ 2Gy/# 80% 79.2 Gy given in 1.8 Gy /day was the maximally well-tolerated dose. Toxicities were significantly higher with 78 Gy given in 2.0 Gy /day than the 79.2 Gy dose level.

68. Dose Escalation using Proton Porton Radiation Oncology Group 95-09 (2005,2008) 393 patients, T1b-T2b and PSA < 15, 58 % low, 33 % intermediate risk. No ADT 70.2 vs 79.2 Gy with proton boost after 50.4 Gy -photon to P&SV. Median follow up 5.5 years. 5-year RFS: Low risk: 84 →98% Intermediate-risk: 79 →91% No OS diff

69. SBRT King et al reported 35-36.2 Gy in 5# resulted in 5 years relapse free survival of 93% with decreased rectal and urinary toxicity. MSKCC Phase I randomized trial is undergoing for SBRT using Image Guided IMRT. 5 mm margin around prostate and 3 mm margin at rectal junction.

70. SEQUELAE OF RT 3DCRT / IMRT Acute and late urinary toxicities similar, grade 3 hematuria-0.5% Stricture -4% and incontinence- 2% (h/o prior TURP)

71. Brachytherapy It is also a dose escalation method when combined with EBRT. Low Risk Disease: Brachy only High Risk Disease: EBRT + Brachy

72. LDR Brachy As Brachy only: I 125 144 Gy , Pd 103 125 Gy . After EBRT 40-50 Gy : I 125 110 Gy , Pd 103 90 Gy . Goals LDR Toxicity V100: 95-99% Acute Urinary Retention V150: <70% Rectal Toxicty V200: <20% Erectile Dysfunction D90: 90-100%

73. HDR Brachy As Brachy only: 9.5Gy twice daily for 2 days or 10.5Gy in 3# over one day. After EBRT: 9.5Gy in 2# over one session. Goals V100: 90-96% V150: <40 % D90 : >90%

74. General Inclusion Criteria: Clinical Stage T1-T3b and selected T4 Gleason score 2-10 PSA No upper limit, but in almost all cases, patient does not have documented distant metastasis (TxN0M0) Exclusion Criteria: Relative Contraindications Severe urinary obstructive symptoms Extensive TURP defect or TURP within 6 month Collagen vascular disease Absolute Contraindications Unable to undergo anesthesia (general, spinal, epidural, or local) Unable to lay flat

75. IODINE 125 PALLADIUM 103 T 1/2 (days) 59.4 16.97 Energy(keV) 27.4 21 Form Seeds Seeds Implant type Permanent Permanent Dose rate 7 19 Mean 0.42 1.3 activity/seed Monotherapy 145Gy mPD 125Gy mPD dose +EBRT dose 110Gy mPD 100Gy mPD TVL(mm) Pb 0.01 0.03 A randomized trial shows no different between two arms using two different isotopes . Pd induced radiation prostatitis is higher than I 125 but it also recover sooner than that.

76. Advantages of EBRT + Brachy Better BED than IMRT Less dose to nearby critical structures Overall treatment time is less than 8 weeks, hence patient is more compliant No issue of prostate motion

77. Procedure

78. Pre Planning and Ultrasound: Obtaining images of the entire prostate, with 5mm spacing between slices; Transfer these images via cable or VCR to the planning system Determination of the volume (in cubic centimeters) of the prostate, using the HWL (Height x Width x Length) x Factor(0.523) for the prostate; Identifying in advance the technical feasibility of the implant (anterior urethral defects,pubic arch interference or micro macro calcifications). Drawing the boundary of the prostate: A new file is created, corresponding to the patient in question; A coordinate system is created from the information of the "template" images superimposed on the TRUS (transrectal ultrasound); Radiotherapist draws the boundaries of the prostate, seminal vesicles, rectum and ureter in each section of the TRUS; Prostate volume is determined by the volumetric reconstruction of the U.S. Distribution and quantity of seeds mCi .

79. Preparation of material for the implant: The charge physicist needs to control and verify the seeds that reach for each patient. It is recommended that the physicist verify at least 10% of the batch using a well chamber and the measure has a limit of 5% difference between the measured activity and the certificate. Standards for sterilization of seeds: The seeds are sterilized in an autoclave system the temperature of 121 centigrade and a pressure of 15 psi for 15 to 30 minutes, or the temperature of 133 Centigrade and pressure of 30 psi for about 3 minutes (“flash”). After sterilization, using Geiger monitor to check radioactivity inside of the autoclave. Positioning the patient on the table: supine and lithotomy position with legs flexed according to the survey pre-planning. Anesthesia, monitoring and premedication

80. Images of the prostate via ultrasound Choose the largest cross section of the prostate, by transrectal ultrasound, as the target volume. Transrectal ultrasound images has a 5 mm separation of each other, and each image is overlap with the image developed by the planning system. It is used to call this planing image as a TEMPLATE IMAGE. Transfer images to the planning system identifying the prostate, urethra and rectum. Revaluate of prostate volume and calculating the number of seeds and needles. Insertion of needles and seeds Insertion of the needles is by the urologist, according to the shape and size of the prostate and activity of the seeds under the guidance of radiotherapist . Identify of each needle in the template and each length to be loaded; Insert of two needles, via trans perineum, approximately 1 to 1.2 cm in the direction of the urethra after 4 and 8 hours as stabilizers .

81. Put the needle on the edge first and place them top to bottom. - Check the positioning of each needle with sagittal images of the ultrasound. The needles placed in the periphery are spaced between 0.5 to 1.0 cm and 0.5 cm inside the periphery of the prostate. The typical number of needles in the periphery is 9 to12 needles. The needles placed in the "Line 1" (the lowest) are separated by 1.0 cm and about 0.5 cm from the anterior rectal wall mucosa. The needles in the central region of the prostate are placed at least 1.0 cm apart from the urethra. The typical number of needles in the central region is 3 to 5. The standard distribution of the loads is 75% -80% of the total activity in the periphery and 20% -25% in the center.

82. Placement of seed s Guided by fluoroscopy and ultrasound at the time the surgery; Using the Mick applicator for the loading of individual seeds in each needle according to the pre-planning and the eventual corrections in the time of implantation. Check the seed deposition with the help of sagittal ultrasound image to the last needle; The physicist and radiotherapist individually confer the number, distribution and spacing of each seed needle immediately prior to their placement, as well as checking the needle by fluoroscopy. At the end of seed deposition, potentially cold areas identified by fluoroscopy and ultrasound should be filled with seeds individually

83. C ystoscopy is performed by an urologist at the end of the introduction of seeds into the prostate. Radiometric survey of the room and the patient - Counting the number of remaining seeds and deployed to confirm the number of seeds initially loaded in magazines. - Monitor the environment, professionals and the patient with the monitor Geiger Muller,

84. Dose analysis A quantitative dose analysis must be carried out for each patient post implantation.

85. Prescribed dose The recommended prescription doses for Iodine-125 are 145 Gy and 110 Gy for monotherapy and boost implants, respectively. The prescription of minimum peripheral dose (mPD) is intended to cover the CTV , and is the reference dose for the treatment. 3.X-ray CT examination is performed immediately after implant and 3 to 5 weeks after . The patient is scanned in a supine position usually with bladder contrasting . Slices with thickness of 3 mm or less are acquired from 2 cm cephalad to the base of the gland to 2 cm caudad to the apex. All of the seeds used in the implant should be encompassed in the scan. ETVs (-Evaluation Treatment Volume) are determined from this scan, as the location of the urethra and the rectum. Due to the difficulty in CT visualization of the urethra, use of Foley catheterization is strongly recommended. The urethra and the rectum contours are drawn as the outer surface of the Foley catheter and the rectal wall, respectively. The CT images are used to create a post-implant treatment plan (post plan). An AP or anterior oblique pelvic radiograph is used to verify the number of sources and this will be recorded. A surview chest CT image is obtained to check any pulmonary migration of the source .

86. Post-Treatment Evaluation Biochemical assessment: Serial PSA determinations – baseline at 3-6 months and then every 6 months and/or as per institutional protocol Physical examination: Role of routine DRE is controversial Quality of Life: Urinary, bowel, and sexual function should be prospectively assessed Post-Treatment Biopsy: Should be reserved for protocol settings or in clinical situations where salvage local therapy is being considered

87. Painful bony mets: External-beam radiation therapy: 20Gy/5# or 30Gy/10 # & 8Gy in single fraction ↓ pain/ stabilizes bone/ ↓ chances of pathological # bisphosphonates: RANKL inhibitors: denosumab

88. CHEMOTHERAPY

89. 1.Docetaxel 2. M i t o x a n t r on e . TAX 327 1006 patients in 24 countries with HRPC were randomized to one of three chemotherapy regimens: Docetaxel every 3 weeks (with prednisone10 mg) for 10 cycles Docetaxel every week (with prednisone 10 mg) for 5 cycles Mitoxantrone every 3 weeks (with prednisone 10mg) for 10 cycles Patients who received Docetaxel every 3 weeks ( with prednisone ) experienced : Improvement in median survival of 2 months (18.9m vs. 16.5 months) Greater PSA decline (45% vs. 32%) Improvement in Pain (35% vs. 22%) S/E were manageable

90. SWOG 9916 N=770 men Dose used: Docetaxel (60mg/m2) & estramustine (280 mg orally 3 times daily from days 1 through 5) vs. mitoxantrone(12mg/m2) and 95 mg twice daily) overall survival favored docetaxel (18.9 months compared with 16 months for mitoxantrone). 20% reduction in mortality in docetaxel &estramustine arm Median time to progression significantly superior in the same arm(6.3 vs.3.2 months) Results Of SWOG & TAX 327 Confirms The Efficacy Of Docetaxel. But Only Question Is That Only 2 Months Survival Increment Is By Use Of Docetaxel.

91. Salvage treatment after first-line docetaxel All patients who receive docetaxel-based chemotherapy for CRPC will progress, thus, there have been many clinical trials investigating the role of salvage chemotherapy. Several groups have used second-line intermittent docetaxel re-treatment in patients who had clearly responded to first-line docetaxel. Newer drugs: Cabazitaxel a taxane derivative Positive results have been published from, phase III trial ( TROPIC trial) comparing cabazitaxel + prednisone vs. mitoxantrone + prednisone in 755 patients with CRPC, who had progressed after or during docetaxel-based chemotherapy . An OS benefit (15.1 vs. 12.7 months, p < 0.0001) was observed in the cabazitaxel arm. As well as PFS (2.8 vs. 1.4 months, p < 0.000). Treatment-associated WHO grade 3/4 side effects developed significantly more often in the cabazitaxel arm, particularly neutropenia and sepsis.

92. Phase 2 trials of docetaxel + atrasentan/ bevacizumab/bortezomid/capecitabine/calcitriol/thalidomide have been completed. Randomized phase 2 trial of thalidomide/docetaxel Phase 2 trial of docetaxel/calcitriol (ASCENT) strongly favoring survival benefit. Mature results are anticipated within the next 3 to 5 years . SPARC: phase III, randomized, placebo-controlled trial uses Satraplatin: novel oral platinum compound Associated with significant PFS improvements in chemotherapy-naive patients with hormone-refractory prostate cancer. Immunologic Therapies Sipuleucel-T is a product freshly prepared for each treatment course consisting of leukapheresed mononuclear cells pulsed ex vivo with a GM-CSF/prostatic acid phosphatase fusion protein. Patients are cytopheresed and dendritic cell precursors isolated prior to fusion protein exposure. Two small randomized phase 3 trials have been conducted with Sipuleucel-T, 9901 and 9902A. Anti CTLA-4 antibody is in clinical trial PROSTVAC-VF TRICOM VACCINE has reported phase 2 data & further studies will ensue.

93. HORMONAL THERAPY MECHANISMS OF ANDROGEN AXIS BLOCKADE

94. The androgen- signaling axis and its inhibitors. Testicular androgen synthesis is regulated by the gonadotropin-releasing hormone (GnRH )–LH axis, whereas adrenal androgen synthesis is regulated by the corticotrophin-releasing hormone (CRH)-ACTH axis. GnRH agonists and corticosteroids inhibit stimulation of the testes and adrenals, respectively. Abiraterone inhibits CYP17, a critical enzyme in androgen synthesis. Bicalutamide , flutamide , and nilutamide competitively inhibit the binding of androgens to androgen receptors ; enzalutamide also blocks the translocation of the ligand bound AR complex to the nucleus and from binding to DNA. DHEA, dehydroepiandrosterone ; DHEA-S, dehydroepiandrosterone sulphate; DHT, dihydrotestosterone; AR , androgen receptor; ARE, androgen-response element.

95. Male sex hormones (testosterone, androgens) are critical to growth of prostate cancer Normalization of PSA < 4ng/ml - 60-70% Tumor masses will decrease by half or more in 30-50% Improvement in symptoms (bone pain, urinary obstruction)- 60% There are four general forms of ADT: Ablation of androgen source Inhibition of LHRH or LH Inhibition of androgen synthesis Antiandrogens Orchiectomy DES Leuprolide Aminogluthemide Cyprotene acetate Goserelin Ketoconazole Flutamide Triptorelin Biclutamide Histrelin Nilutamide Cetrorelix Abarelix

96. Side-effects of hormonal therapy Castration Loss of libido Erectile dysfunction Hot flashes (55–80% during ADT) Gynaecomastia and breast pain Increase in body fat Decrease in bone mineral density Osteoporosis Muscle wasting Anaemia (severe in 13% CAB) Cognitive decline Oestrogens Cardiovascular toxic effects (AMI, CHF, CVA, DVT, pulmonary embolism) LHRH agonists Flare phenomenon due to initial rise of testosterone Might worsen symptoms Costly

97. Enzalutamide : A novel anti-androgen that blocks AR binding, nuclear translocation and transcription. Enzalutamide is used as a once-daily oral treatment. AFFIRM study in 2012 randomized 1,199 patients with metastatic CRPC in a 2/1 fashion between enzalutamide or placebo. (The patients had progressed after docetaxel treatment). After a median follow-up of 14.4 months, the median survival in the enzalutamide group was 18.4 months compared to 13.6 months in the placebo arm (HR: 0.63, p < 0.001). This led to the recommendation that the study be halted and unblinded. The benefit was observed irrespective of age, baseline pain intensity, and type of progressio n.

98. CYP17 inhibitor. It is used once daily combined with prednisone twice daily (10 mg/ day). large phase III COU-AA-301 trial used a total of 1,195 patients with metastatic CRPC were randomised in a 1/1 fashion between abiraterone acetate or placebo, In patients with progressive disease after docetaxel therapy the median survival in the abiraterone group was 15.8 months compared to 11.2 months in the placebo arm (HR: 0.74, p < 0.001). The benefit was observed irrespective of age, baseline pain intensity, and type of progression. most common grade 3/4 side effects did not differ significantly but mineralocorticoid-related side effects were more frequent in the abiraterone group, mainly grade 1/2 (fluid retention, oedema or hypokalaemia). As of today, the choice between third-line hormonal treatment (using enzalutamide or abiraterone) or second line chemotherapy (cabazitaxel) remains unclear with no clear decision-making findings published . Abiraterone Acetate

99. Bone-seeking radiopharmaceuticals (samarium-153- EDTMP, strontium-89): Three radiopharmaceuticals are currently FDA-approved for the palliative treatment of painful bone metastases 1. phosphorus-32 2.strontium-89 3.samarium-153-EDTMP. Myelosuppression is the predominate toxicity associated with all of the bone seeking radioisotopes .

100. Schedule Frequency First follow up 4-6 weeks after RT 0-1 years Every 3-4 months 2-5 years Every 6 months 5+ years Annually Examination History & Physical Examination Complete History & Physical Examination Annual DRE Laboratory Tests PSA every 6-12 months for 5 years and then annually Imaging Studies Based on clinical indication only Follow Up

101. THANK YOU!