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CARCINOMA PROSTATE- Dr Manoj Kumar B, PGI

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  • Unenhanced CT scan in 78-year-old man with prostate cancer, Gleason score of 34 at biopsy, PSA level of 21 ng/mL, and palpable tumor shows enlarged prostate with evidence of gross tumor ECE (arrow) along left posterolateral margin of the gland.

Transcript

  • 1. CARCINOMA PROSTATE AND IT’S MANAGEMENT
    • Mod: Dr S. Ghoshal
    • 18.09.08
  • 2. ANATOMY
    • Male accessory reproductive organ
    • Conical fibro-muscular-glandular organ, surrounding the proximal urethra
    • Situation – shape-dimension- capsules
    • Parts- Apex/ base/ Ant./Post./ 2 Inferolat. & post. surfaces
    • Vascular system-Prostatic venous plexus & Batson plexus
    • Lymphatic drainage- Regional / Distant LNs- pathways:
    • Laterally to the hypogastric and internal iliac nodes (primary)
    • Inferiorly to the pudendal and then subsequently to the obturator fossa (secondary)
    • Superiorly from the top of the prostate over the bladder to the external iliac nodes, a few centimeters below the bifurcation of the common iliac artery (tertiary)
    • Posteriorly alongside the rectum to the presacral nodes of the promontory (quaternary)
    • Lobar & Zonal anatomy ( Mc Neal )
    • Peripheral zone : 60- 70% of Ca P origin
    • Transitional zone: 10-20% of Ca P origin
    • Central zone: 5-10% of Ca P origin
  • 3. Lobes Zones
  • 4. EPIDEMIOLOGY
    • 5 th most common cancer
    • 33% of all newly diagnosed cancers
    • 2 nd most common cancer in men- 29% of all male cancers
    • 2 nd leading cause of cancer death in men in western world
    • World wide incidence- 25.3 per lakh ( Vera Nelson, RRCR, vol. 175, 2007 )
    • Higher incidence – Scandinavia, North America, Australia, western and northern Europe
    • Low incidence- Asian countries
    • India- 4% of all male cancers
  • 5. ETIOLOGY
    • Age related , racial-ethnic and geographical variation suggesting primary environmental and genetic influence
    • RISK FACTORS
      • Advanced age
      • Diet- Higher fat and zinc/ selenium/ lycopene/ vit.E
      • Higher BMI
      • F/H – hereditary-1 st degree relative– 5 to 11 fold risk
      • Genetic- 1q24-25 and familial link with HPC1 , 5-α Reductase Polymorphism (SRD5A2 gene)/Cytochrome P459C17 & Cytochrome P4503A4/Androgen receptor- CAG repeat
      • Histologic precursors- PIN(35% within10 yr) and AAH
      • Hormonal
      • Race
      • Environmental/ occupational- cadmium, heavy/ rubber industries
      • ? BHP/ Vasectomy/ STD/ Sexual promiscuity
    • No a/w cigarette smoking/ alcohol
  • 6. NATURAL HISTORY
    • LOCAL GROWTH PATTERN
      • Almost all prostatic carcinomas (>70%) develop in the PZ and BHP (>90%) arises from the TZ ( McNeal)
      • Small tumors tend to occur in the anteromedial gland, adjacent to the fibromuscular stroma, whereas larger, more advanced T stage tumors are often located in the posterior gland near the prostatic capsule
      • Multifocality is characteristic of prostate cancer -77% ( Jewett )
      • TZ tumors - demonstrate a lower frequency of ECE and may harbor large volumes of disease with relatively high PSA levels but remain confined to the prostate. Despite a high PSA value (>10 ng/mL), considered to have a favorable prognosis
      • PZ cancers - spread along the capsular surface of the gland, and may extend through the capsule of the gland, invade seminal vesicles and periprostatic tissues, and involve the bladder neck or the rectum.
  • 7.
      • Clinical stage closely correlates with risk of ECE and disease progression
      • Incidence of microscopic tumor extension beyond the capsule of the gland (at the time of RP) in patients with clinically organ-confined disease ranges from 8% - 57%
      • The incidence of SVI also is associated with the level of PSA, the Gleason score, and the clinical stage
    • Lymphatic spread
      • Obturator node - commonest and earliest / Iliac/ Presacral
      • Common iliac/ inguinal/Paraaortic
    • Hematogenous distant metastasis
      • Spine/ pelvis/ femora/ lung/ liver / adrenals
  • 8. CLINICAL MANIFESTATIONS
    • EARLY STAGE
        • Asymptomatic
        • Cancer is in the peripheral zone
    • LOCALLY ADVANCED DISEASE
        • Obstructive / irritative voiding
        • Retention of urine
        • Hematuria
        • Renal failure
        • Pelvic pain
    • METASTATIC DISEASE
        • Bone pain
        • Spinal cord compression symptoms
        • Paraperesis
  • 9.
    • History- Urinary status/ sexual function/ skeletal symptoms/ co-morbidities
    • OBTRUCTIVE SYMPTOMS: PROSTATISM
      • Symptom complex- initially
        • Urinary hesitancy
        • Diminished force of urine stream
        • Intermittancy
        • Sense of incomplete voiding
      • Loss of bladder detrusor compliance
        • Urgency
        • Frequency
        • Nocturia
        • Incontinence
        • Acute retention may occur
    • LUTS : constellation of obstructive symptoms often a/w BHP /mechanical or functional disorder of UB
  • 10.
        • Hematuria- prostatic urethra/ trigone involvement
        • Hematospermia
    • Extra prostatic spread- often asymptomatic/ extensive dis.
    • Rectal involvement-
        • Hematochezia
        • Constipation
        • Intermittent diarrhoea
        • Decreased stool caliber
        • Abdomino-pelvic pain
    • Renal impairment due to prolonged BOO
    • Fluid retention/ electrolyte imbalance
  • 11.
    • Involvement of neurovascular bundles/ UGD/ corporeal bodies – Impotence/ pelvic pain/ priapism
    • Advanced disease- metastatic symptoms
      • Bony- pain / pathological fracture/ Spinal tendernesss
      • Spinal cord compression- neurological deficits/ sensory-motor changes/ bladder-bowel dysfunction
      • Pelvic / Paraaortic LAP- edema of abdominal wall, genitalia or lower extrimities/ mass abdomen
      • Adrenal/ lung/ skin mets
      • PNS- SIADH/ Cushing syndrome/ Hematologic
  • 12. PHYSICAL EXAMINATION
    • G/E
    • Systemic examination
    • DRE - cornerstone of the physical examination/ instrumental in staging
      • Sim’s lateral prone/ Lithotomy/ Knee-chest/ Standing
      • Organ palpation:
        • Craniocaudal and transverse dimension
        • Consistency/ Sensitivity/ 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
        • SVI- Firmness extending superior to the prostate gland
  • 13.
          • Positioning
    • DRE
      • Specificity- 50% and Sensitivity- 70%
      • Only 25-50% of men with an abnormal DRE have cancer
      • DRE+PSA specificity 87%
  • 14. 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 (PSA >20)
      • Magnetic resonance imaging with endorectal coil
  • 15. 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±0.8 ― 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%
      • Clinically localized tumor ― 81-97% and 40% are not palpable
      • Pathologically localized tumor ― 36-91%
      • Carcinoma with normal PSA ― 25%
  • 16.
    • Age specific PSA
      • Age PSA Range %
      • 40-50 0-2.5 4-10 25
      • 60-70 0-4.5 >10 60 (localized 50%)
      • 70-80 0-6.5 high suspicion of carcinoma
      • >50 ↑ LN mets/ bone mets
      • disseminated disease
    • 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
  • 17.
    • Rule out the possibility of ca
    • Gives idea about intraprostatic volume of disease
    • Decision regarding Bx and treatment
    • Monitoring response to therapy
    • Base line for follow up and detecting recurrence after therapy
    • Detection yield
      • DRE+PSA = 4.7-5.8%
      • PSA+DRE+TRUS = 60%
    • Biochemical failure: PSA relapse- rise or persistently detectable serum PSA following definitive treatment (30-40% in localized t/t)
      • Post op: > 0.2 ng/ml in serum PSA
      • Post RT:
        • ASTRO consensus - 3 consecutive PSA rises with the time of failure backdated to halfway b/w the PSA nadir and the first PSA rise
        • Phoenix consensus - PSA rise ≥ 2 ng/ml above the nadir PSA (Standard def n for BCR post RT with or without short term HT)
        • (Nadir + 2 definition ) Sensitivity-64% Specificity-78%
        • ( Mack Roach, IJROBP, 2006 )
    • DRE+Bx = 22%
    • PSA+DRE+Bx = 48%
  • 18. TEMPORAL VARIATION
    • PSAD (PSA Density)
      • Cancers produce less PSA per cell than nonmalignant prostatic tissues
      • Calculated by dividing the serum PSA concentration by the volume of the prostate gland measured by TRUS
      • A higher PSA density is a/w malignancy
      • Important in elderly patients
      • BHP ― 0.3ng/ml/gm
      • Ca prostate― 3.3ng/ml/gm
      • PSA rises @ 3.5ng/ml/gm of intacapsular cancer regardless of ECE
    • PSAV (PSA Velocity)
      • Serial PSA measurements and calculate the rate of rise in PSA
      • A rate of rise of >0.75 ng/ml/yr a/w a higher frequency of cancer
      • Important for young patients
  • 19.
    • PSA rises after
      • DRE/ ejaculation/ cystoscopy/ message (sampling 1 week later)
      • Biopsy / TURP (sampling 4 week later)
    • Ratio of free to total PSA(% free PSA) lower for carcinoma(<7%)
    • Complexed-to-total ratio higher and free PSA lower for cancer
    • PROSTATIC ACID PHOSPHATASE (PAP) (N- 0-5.5 u/l)
      • Sensitivity- 10% Specificity-90%
      • Abnormal PAP correlates with higher tumor stage T 3 , T 4 , higher grade, pretherapy serum PSA
      • Affected by circadian rhythm, prostatic message, Sx manipulation and BHP
    • ACR & AUA recommendation
      • Annual DRE+ PSA screening for men>50 yr with life expectancy >10 yrs.
      • At age of 45 yr in men with african-american origin or with F/H
  • 20. IMAGING
    • CXR
      • Pulmonary metastasis
      • Miliary pattern
    • Axial skeletal survey : Specific sites of bony pain
      • Osteoblastic secondaries
    • USG abdomen-pelvis: HDUN/ large PVR/ RPLAP/ Liver mets.
  • 21. 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)
  • 22.
    • Once gland volume has been obtained, one can calculate derivatives such as the PSA density (PSAD = serum PSA/gland volume)
    • Predicting a positive cancer diagnosis on repeat biopsy Sensitivity – 75-86% & Specificity- 41-44% ( Djavan et al, 2000 )
    • All hypoechoic lesions within the PZ should be noted and included in the biopsy material
      • Hypoechoic-14-39%(~40%)
      • Isoechoic- 14-29%
      • Hyperechoic-1%
    • TZ BPH nodules are typically hypoechoic but may contain isoechoic or even hyperechoic foci
      • A hypoechoic lesion is malignant in 17% to 57% of cases ( Frauscher et al, 2002 ), highlighting the need to biopsy these lesions but recognizing they are not pathognomonic for cancer as once thought.
  • 23.
    • Extraprostatic extension
      • Sensitivity-66% Specificity- 46% Accuracy- 58%
    • Seminal vesicle invasion
      • Echogenic abnormalities
      • Ant. displacement and enlargement of SV
  • 24.
      • Evaluation of an abnormal DRE and/or abnormal PSA
      • Measurement of prostate volume for treatment planning and/or monitoring
      • 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
        • (ACR & AUA)
        • 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
  • 25.
    • Other uses
      • Staging of rectal carcinoma and treatment
      • Suspected congenital anomaly of the prostate, rectum, seminal vesicle or surrounding tissue
      • Diagnosis and/or monitoring of azoospermic or oligospermic patients with palpable vasa and low ejaculate volumes
      • Evaluation of LUTS (e.g., pelvic pain, prostatitis/prostadynia, obstructive and irritative voiding symptoms)
    • Experimental, investigational or unproven
      • Use as a stand-alone screening tool for prostate or rectal ca
      • Transrectal high-intensity focused ultrasound ( HIFU ) treatment
  • 26.
    • PSA DRE TRUS
    • Sensitivity 96% 87% 84%
    • Specificity 14% 60% 41%-67%
    • PPV 32% 48% 52%
    • NPV 88% 92% 91%
    • ( Aarnink, et al., 1998 )
  • 27. CT SCAN
    • Primary role
      • Size determination of the gland
      • Assess pelvic LN metastasis
      • Treatment planning in RT
      • EPE:
        • 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
  • 28.
    • 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
  • 29. 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%
    • Nodal involvement sensitivity increases to 96% with the use of IOLSPNP
    • Endorectal surface coil MRI- accuracy of 54-72% staging the primary and detects SVI and ECE
  • 30.
    • 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
  • 31. MRSI
    • Spectroscopy principle: The electron cloud surrounding different chemical compounds shields the resonant atoms of interest to varying degrees depending on the specific atomic structure of the compound
      • Glandular Citrate concentrations 240 to 1,300 times greater than blood plasma concentrations. High levels of citrate -Peripheral zone and lower levels in the transition and central zones.
      • Choline
      • Tumor: A significant reduction in prostate citrate and a significant increase in prostate choline levels relative to the normal peripheral zone
      • Metabolic map of the prostate corresponding to normal and abnormal metabolic activity that can be used to pinpoint the location of prostatic tumors
  • 32.
      • 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
  • 33. 99 TC BONE SCAN
    • Clinically apparent metastatic disease limited to bone in 80-85% of patients of metastatic ca prostate
    • A close correlation exists between pretreatment PSA level and incidence of abnormal bone scan results
    • Osteoblastic secondaries
    • MC sites of metastasis
      • Vertebral column- 74%
      • Ribs- 70%
      • Pelvis- 60%
      • Femora- 44%
      • Shoulder girdle-41%
  • 34.
    • 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
      • ACR recommendation : for pretreatment staging of clinically localized prostate cancer, bone scan can be omitted in case of low-risk patients with PSA of ≤10 ng/mL or GS 2 to 6
    • Post therapy: Skeletal symptoms in a/w ↑PSA level
    • False +ve
      • Fractures/ Arthritis / Paget’s disease
  • 35. PATHOLOGY
    • Normal prostatic histology- composed of PSA, PAP and mucin secreting secretory cells
    • Primary
      • Epithelial Stromal
      • Adenocarcinoma (95%) RMS (42%, children <10 yrs)
      • TCC LMS (26%, > 40 yrs)
      • SCC
      • NET- carcinoid
      • Adenoid cystic ca
    • Secondary- direct invasion from UB, colon/mets from lung, melanoma/ systemic lymphoma
    • Adenoca arises from acinar epithelium of PZ
      • Premalignant lesion
        • Atypical adenomatous hyperplasia
        • Duct acinar dysplasia – PIN and CIS
  • 36. GLEASON SYSTEM
    • Based on the degree of glandular differentiation and overall pattern of tumor growth
    • Adenocarcinoma- well/ mod./ poorly diff. according to the cellular characteristics i.e. nuclear content, no. of nuclei, pleomorphism, gland formation and stromal invasion
    • 5 patterns of growth
    • Histologic variation in tumor, so two predominant patterns are recorded for each case
      • Primary/ predominant pattern (1-5)
      • Secondary / lesser pattern (1-5)
    • GLEASON SCORE
      • Sum of the 1º and 2º patterns (2-10)
      • >50% ca contain ≥2 patters
      • One of the strongest predictors of biological behaviour, invasiveness and metastatic potential
  • 37. GLEASON GRADING It is important to recognize Gleason pattern 4 tumor because tumors with this pattern have a significantly worse prognosis than those with pure Gleason pattern 3 ( McNeal et al, 1990 ). Tumors with Gleason score 4 + 3 = 7 have a worse prognosis than those with Gleason score 3 + 4 = 7 ( Chan et al, 2000 ) GS Gleason’s Pattern Histo. Grade Differentiation 10 yr Progression (%) 2, 3, 4 1, 2 I Well <25 5, 6, 7 3 II Mod. 50 8, 9, 10 4, 5 III Poorly 75
  • 38. TNM STAGING SYSTEM
  • 39. TNM STAGING SYSTEM
    • PRIMARY TUMOR (T)
      • TX -Primary tumor cannot be assessed.
      • T0 -No evidence of primary tumor
      • T1 -Clinically inapparent tumor neither palpable nor visible by imaging
        •   T1a -Tumor incidental histologic findings in ≤5% of tissue resected  
        • T1b -Tumor incidental histologic finding in >5% of tissue resected  
        • T1c -Tumor identified by needle biopsy (e.g., because of elevated PSA)
      • T2 -Tumor is confined within prostate.  
        • T2a -Tumor involves one half of a lobe or less
        •   T2b -Tumor involves more than one half of lobe, but not both lobes  
        • T2c -Tumor involves both lobes
      • T3 Tumor extends through the prostate capsule.  
        • T3a -Unilateral extracapsular extension  
        • T3b -Bilateral extracapsular extension  
        • T3c -Tumor invades seminal vesicle(s)
      • T4 -Tumor is fixed or invades adjacent structures other than seminal vesicles.  
        • T4a -Tumor invades bladder neck, external sphincter, or rectum.  
        • T4b -Tumor invades levator muscles or is fixed to pelvic wall, or both.
    • NODE (N)
      • NX -Regional lymph nodes cannot be assessed.
      • N0 -No regional node metastasis
      • N1 -Metastasis in single lymph node, ≤2 cm
      • N2 -Metastasis in a single node, >2 cm but ≤5 cm
      • N3 -Metastasis in a node >5 cm
      • METASTASIS (M)
        • MX -Presence of metastasis cann’t be assessed
        • M0 -No distant metastasis
        • M1 -Distant metastasis  
          • M1a -Nonregional LNs  
          • M1b -Metastasis in bone(s)  
          • M1c -Metastasis in other site(s)
    • STAGE GROUPING
    • I T1a N0 M0 G1
    • II T1a N0 M0 G2,3–4
    • T1b N0 M0 Any G
    • T1c N0 M0 Any G
    • T1 N0 M0 Any G
    • T2 N0 M0 Any G
    • III T3 N0 M0 Any G
    • IV T4 N0 M0 Any G
    • Any T N1 M0 Any G
    • Any T Any N M1 Any G
  • 40. TREATMENT
    • Depends on stage, patient's age and GC
    • EARLY
    • LOCALLY ADVANCED
    • METASTATIC
    • 3 risk group
    • Stage Initial PSA Gleason gr.
      • 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
  • 41. WATCHFUL WAITING
    • Low risk cases
      • Life expectancy < 10 yrs
      • Elderly patients
      • Low volume disease (<2.5cc) with PSA <10 and GS 2-6
      • Probability of progression of disease <2%/yr
    • An active decision not to seek cure
    • Palliative, not curative
    • As disease progresses supportive measures initiated
    • If a man lives long enough he will die from prostate cancer
    • Disease volume (cc) LN mets (%)
      • <2.5 <5
      • 2.5-7 25-26
      • 7-13 62
    • GS 10 yr survival (%) LN mets (%)
      • 2-6 85 <6
      • 7 69 32
      • 8-10 20 76
  • 42. RADICAL PROSTATECTOMY
    • Selection:
      • <60 yrs
      • Good GC
      • Life expectancy >10yrs
      • No life threatening ancillary disease
    • Advantages
      • Curative
      • Removal of entire prostate and seminal vesicle
      • Pelvic lymphadenectomy for staging
      • Preservation of distal sphincter
      • Preservation of cavernosal nerves-to prevent impotence
      • Definitive pathologic information
      • Less chance of biochemical failure
    • Complications
      • Sexual dysfunction (20-100%)
      • Urinary Incontinence (4-70%)
      • Bleeding
    • Approaches
      • Retropubic
      • Transperineal
      • Laproscopic (pure, robot assisted)
      • Stricture (0-12%)
      • Mortality (<1%)
  • 43.
    • STAGE LOCAL CONTROL at 5 yrs
    • T 1a - T 2a > 95%
    • T 1b - 2b > 92%
    • T 3a > 82%
    • Overall biochemical relapse rate 17%
    • PSA relapse free survival rates 84% - 5 yr, 74% -10 yr and 66% for 15 yrs
    • Factors predictive of high chances of local recurrence
      • Larger volume , ECE
      • Higher grade (GS 8-10)
      • Positive sx margins
      • pT3a or pT3b disease
  • 44. RADIOTHERAPY
    • Radical
    • Adjuvant
    • Palliative
    • EBRT- Conventional / Conformal
    • Brachytherapy
  • 45. RADICAL EBRT
    • Indication:
      • Age<70 yrs
      • Stage T 1b , T 2 , T 3
      • LN involvement detected by nodal sampling
      • Risk of LN involvement ≥ 15%
      • Documented SVI
      • Gleason score ≥6
      • PSA ≥ 20 ng/ml
    • Treatment Volume- Prostate, SV, prostatic urethra and margin of 1-1.5cm for T 1- T 2 lesion and pelvic LNs to be included if the lesion is T 3
    • Positioning
    • Localization
    • Treatment planning
    • Field selection: Four-field box technique
  • 46.
    • Field size : 15X15 cm
      • 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
    CONVENTIONAL EBRT PORTALS
  • 47.
      • 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
  • 48.
    • Prostate+ SV- 12X14 cm
    • 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
  • 49.
    • Other methods of boost-
      • Rotational arc- bilateral 120º arc
      • Six field techniques- opposed lateral fields and two sets of opposed oblique fields angled ±45º
      • Noncoplanar multiple fields- lateral fields and two ant. inf. oblique fields
    • Verification
    • Dose-
      • 70-72.4 Gy/7wk@ 1.8-2 Gy/#
      • 45-50 Gy/5wk to whole pelvis followed by a boost of 20 Gy to the prostate
  • 50.
    • Advantages of pelvic EBRT:
      • Primary lesion along with periprotatic tissue and pelvic LNs are homogenously irradiated
      • Surgical complication avoided
      • Good local control
    • Based on stage
      • T 1a – 66-70 Gy
      • T 1b, c T 2b – 70-72 Gy
      • T 2c – 74 Gy
  • 51. CONFORMAL RT - 3DCRT
    • Three dimensional imaging and treatment planning
    • CT-based images referenced to a reproducible patient position are used to localize the prostate and normal organs and to generate high-resolution 3D reconstructions of the patient
    • Treatment field directions are selected using BEV techniques and the fields are shaped to conform to the patient's CT-defined target volume, thereby minimizing the volume of normal tissue irradiated
    • Dose information for entire target volume and normal tissue
    • Ability to increase total radiation dose
    • Steps
      • Immobilization, Simulation, and CT Scanning
      • Isocenter placed according to anatomic landmarks near the center of the prostate gland: midline, at the caudal aspect, and ~ 5 cm posterior to the symphysis pubis
  • 52.
      • Target and Normal Tissue Contouring
        • CTV = Prostate + SV
        • PTV = CTV +a margin to account for physical uncertainties including setup reproducibility, inter- and intrafractional organ motion (1-cm margin added to the CTV to form the PTV in all directions except posteriorly at the interface with the rectum, where the margin is reduced to 0.6 cm)
      • Beam Selection and Planning
      • Standard 3D conformal beam arrangement- six coplanar fields, including two lateral, two anterior and two oblique beams
      • Conformal apertures drawn around the PTV adding a margin of ~5 to 6 mm in the axial directions to account for beam penumbra
      • Beam shaping, MLCs used
      • Dose distribution calculated for a few representative planes, typically transverse, coronal, and sagittal planes through the isocenter
      • DVH generated for the PTV, femoral heads, and rectum, bladder and bowel
  • 53.
      • 6-field plan, the two lateral beams typically deliver ~1/2 of the dose to the isocenter with the four oblique beams contributing the rest. The beam weights of the anterior oblique and posterior oblique beams adjusted to obtain a uniform dose within the PTV and to place the hot spots away from the rectum
      • The plan normalized so that the prescription isodose (100%) covers the PTV
      • Normal tissue dose limits-
        • Rectal wall volume not ≥ 30% receiving ≥ 75.6 Gy
        • Femurs to ≤68 Gy (90%)
        • Large bowel maximum dose ≤ 60 Gy (79%)
        • Small bowel ≤ 50 Gy (66%)
  • 54.
      • Careful about: Immobilization/ precise target volume definition / Tumoricidal dose to the tumor while minimizing dose to the normal tissue
    • GTV = Prostate CTV= GTV+0.5-0.8 cm margin PTV= CTV+0.8-1 cm margin
    • GTV= Prostate+SV in case of intermediate and high risk cases
    • Expected movement with respiration
      • Craniocaudal – 1-7 cm A-P - 0.5 cm Lateral- 0.7cm
  • 55. GTV+SV GTV+ SV, PTV, CTV LN GTV P+SV, CTV P+SV CTV P+SV
  • 56. 3DCRT FIELDS ARRANGEMENTS
  • 57.
    • AP
    • LATERAL
  • 58. IMRT
      • Radiation beam intensity or ‘Fluence’ varies across the fields
      • Delivery of an IMRT intensity pattern requires a computer-controlled beam-shaping apparatus on the linear accelerator known as MLC which consists of many small individually moving leaves or fingers that can create arbitrary beam shapes
        • Static mode - “STEP AND SHOOT” which consists of multiple small, irregularly shaped fields delivered in sequence
        • Dynamic mode - Dynamic multileaf collimation with the leaves moving during treatment to create the required irregular intensity patterns
      • Defining dose ‘Constraints’ or ‘Objectives’ for the target and normal tissues, which describe the desired dose distribution in IMRT planning
  • 59.
      • Constraints: Maximum or minimum dose limits on targets and dose-volume limits on normal tissues
      • Mathematical optimization of the radiation intensities of many small ‘beamlets’ within each treatment field which result in a set of intensity patterns for the treatment fields and a dose distribution with characteristics as close as possible to the constraints entered
      • Dose delivery carried out by setting each field to desired gantry angle with prescibed leaf position and MU
      • Isodose distribution- concave / convex
      • T/t verification with weekly portal films/ online portal imaging
      • Short course IMRT- 70 Gy/28#/5 1/2 weeks @ 2.5Gy/#
      • Low risk- 70-75 Gy Intermediate and high risk- 75-80 Gy
      • 5 fields: Ant., 2 lateral, 2 ant. oblique
      • Prescribed isodose 82-90%
  • 60. IMRT PHASE
  • 61. CONVENTIONAL RT CONFORMAL RT
    • ADVANTAGES
      • Time tested
      • Easy to plan and execute
      • Time saving in busy setting
      • Cost effective
    • DISADVANTAGES
      • Normal tissue more irradiated
      • Dose escalation not possible
    • ADVANTAGES
      • Better sparing of normal tissue
      • Dose can be escalated
      • 3D planning
    • DISADVANTAGES
      • Interphysician variability in target delineation
      • Chance of missing tumor due to close margin
      • Longer planning time
  • 62. SEQUELAE OF XRT
    • 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%)
    • 3DCRT/ IMRT
      • Acute and late urinary toxicities similar, grade 3 hematuria-0.5%
      • Stricture -4% and incontinence- 2% (h/o prior TURP)
  • 63. BRACHYTHERAPY
    • What
    • Types : Permanent/ Temporary (LDR and HDR)
    • Isotopes
    • Why-
      • Prostate has slow growth which remains localized for a long period
      • Small t/t volume
      • Potency well maintained with minimal complications
      • Older patients>60 yr, less tolerace to high dose XRT
  • 64.
    • Selection:
      • Life expectancy >10 yrs
      • Biopsy proven adenocarcinoma
      • Stage T 1 ,T 2a
      • Grade : Gleason sum 2-6
      • PSA ≤ 10 ng/ml
      • Prostate volume < 60 cc
      • No e/o pelvic LAP/ Negative bone scan/ No prior TURP
      • Brachy+ XRT: T 2b , T 2c , GS = 7-10, PSA > 10 ng/ml
      • Brachy+ XRT+ Hormonal t/t : Initial large prostate > 60 cc
    • Exclusion
      • Life expetancy < 5 yrs, large/ healed TURP defect, distant mets, unfit for anesthesia/ Sx
  • 65.
    • Relative C/I
      • Large median lobe
      • High GS
      • H/o multiple pelvic surgeries
      • DM with healing problems
      • SVI, ECE
      • Apical lesion
      • Gland size > 60 cc or pubic arch interference
      • Prior pelvic RT
  • 66. RADIOISOTOPES IODINE 125 PALLADIUM 103 IRIDIUM 192 T 1/2 (days) 59.4 16.97 73.83 Energy(keV) 27.4 21 340 Form Seeds Seeds Seeds Implant type Permanent Permanent Temporary Dose rate 8 20 Variable Mean activity/seed 0.42 1.3 Monotherapy dose 145 125 Variable (~600) +EBRT dose 110 100 20-25 TVL(mm) Pb 0.01 0.03 HVL-4.5 mm
  • 67.
    • Palladium 103 :
      • Higher initial dose rate
      • More appropriate for rapidly proliferating tumors
      • Lower energy , greater attenuation of dose, rapid dose fall off, so seed spacing not >1.7 cm
      • Lesser late complications
      • Disadvantages: Expensive, not universally available
    • TECHNIQUE
      • TRUS and template guided implantation
      • Templates: Syed- Neblett template or MUPIT
      • Method –
        • Seattl e’s Preplanned transperineal implantation technique
        • Intraoperative planning techniques
  • 68. PREPLANNED TRANSPERINEAL TECHNIQUE
    • Volume study- TRUS imaging is obtained before the planned procedure to assess the prostate volume ( Holm et al )
    • Seed selection- isotopes/ loose or stranded/activity
    • Treatment planning- A computerized plan is generated from the transverse ultrasound images, producing isodose distributions and the ideal location of seeds(at 1 cm interval) within the gland to deliver the prescription dose to the prostate
      • Seed strength : I 131 – 0.41 mci, Pd 103 – 1.32 mci
      • Prescription dose: prescribed at MPD
      • Loading techniques
      • Post plan -to confirm the dose delivered to the prostate as well as evaluate the dosimetry to the OAR
    • Implant procedure
  • 69.  
  • 70.
    • Precautions
      • Total exposure to any individual from patient shouldn’t >0.5 rem over the life span of the implant
      • Keep away from pregnant lady, children < 2months, to abstain for 2-3 weeks and to use barrier contraceptives for few weeks
    • Temporary implants:
      • Ir 192 seeds in plastic ribbon/ 10-15 needles left for 3 days
      • Disagreement b/w pre implant and post implant dose distribution
      • Formation of hot and cold spots, source anisotropy, low energy, radiation is attenuated along the length of seed resulting in cold spots>50% at ends
  • 71.
    • Dose: Brachy Brachy+ EBRT
      • I 12 5 145 Gy 110Gy+ 45-50 Gy
      • Pd 103 125 Gy 100 Gy+ 45-50 Gy
      • Ir 192 20-25 Gy 4-6Gy/# 6 hrs apart, 2#/day
    • Complications
      • Transient urinary morbidities- urethritis/prostatitis/dysuria postimplant 2-3weeks and peaks in 3-4 months
      • Incontinence if prior TURP
    • Decreased chances of impotency
    • Rectal complication similar as with EBRT
  • 72. TRUS GUIDED HDR INTERSTITIAL BRACHYTHERAPY
  • 73.  
  • 74. ADJUVANT RADIOTHERAPY
      • Increased local control eradicating microscopic periprostatic disease/ decresed distant mets/ improved survival
    • 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 mets
      • Dose- 45-50 Gy/20-25#/4-5weks f/b 18 Gy with b/l 120º arc rotation boost to the prostate bed
  • 75.
    • Local failure as a function of site and post op RT
      • Site Without RT (%) With RT(%)
      • SVI + 45 14
      • SVI ― 25 4
      • Capsule + 31 12
      • Capsule ― 35 12
      • Margins + 25 1
      • Margins ― 44 0
  • 76. METASTATIC CA PROSTATE: PALLIATIVE RT
    • Locally advanced / unresectable
    • Hormone failed patients
    • Painful bony mets
      • 20Gy/5# or 30 Gy/10# or 8Gy SF
      • ↓ pain/ stabilizes bone/ ↓ chances of pathological #
    • Multiple painful sites/bony mets
      • Hemi body irradiation– 6 Gy to upper1/2, 8 Gy lower ½ as SF with a gap of 2-3 weeks b/w two treatment and complete pain relief 70-80% within 4 weeks
    • Cord compression
      • Palliative XRT
      • Systemic therapy
          • Sr 89 ― calcium analogue ß emitter with energy of 1.43 MeV, t 1/2 50.5 days , 4 mci IV, response in 20-50% in 4-15 months
          • P 32 ―delayed response and more toxic
  • 77. MECHANISMS OF ANDROGEN AXIS BLOCKADE
    • Male sex hormones (testosterone, androgens) are critical to growth of prostate cancer
    • Hormonal therapy is 1st line therapy
    • 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
  • 78.
    • Effects of androgen deprivation
    • Bilateral orchiectomy - testosterone ↓ by 90% within 24 hrs of surgery
      • One year survival rate of 73 % and a five-year survival rate of 35 % in Stage IV ( CA Cancer J Clin 2002;52:154-179, VACURG study,1967 )
    • Nonsteroidal antiandrogens – increase LH and testosterone levels
    • Antiandrogens can act agonistic on some tumors; antiandrogen withdrawal results in decline of PSA level in 15% to 30% of patients
    • Bicalutamide monotherapy appears to have efficacy equivalent to that of medical or surgical castration for locally advanced or metastatic prostate cancer
    • All LHRH agonists induce a testosterone increase on initial exposure. Co-administration of an antiandrogen functionally blocks the effects of testosterone.
  • 79. Strategies for Androgen Deprivation
  • 80. COMBINED ANDROGEN BLOCKADE
    • Blocks androgen production from the testes (95%) and the adrenals (5%)
    • LHRH agonists + antiandrogen (flutamide, bicalutamide, nilutamide)
    • Have not been shown to be superior to LHRH therapy alone
    • Higher cost and more side effects than LHRH therapy alone
    • DES 1-3 mg TDS
    • LHRH agonists
      • Pitutary desensitization by altering pulsatile release of LHRH
      • Diminished LH
      • Fall in Testosterone <50ng/ml
      • Advantages : Less CVS toxicities
    • Less chances of gynaecomastia
    • Anti-androgen
      • Competitively inhibits DHT receptors -Flutamide 250 mg TD and Biclutamide 50 mg OD
      • With hormonal ablation complete androgen blockage
  • 81. SIDE-EFFECTS OF HORMONAL THERAPY
    • Castration
      • Loss of libido
      • Erectile dysfunction
      • Hot flashes (55–80% during ADT)
      • Gynaecomastia and breast pain (49–80% DES, 50% CAB, 10–20% castration)
      • 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
  • 82.
    • Antiandrogens
      • Steroidal
        • Pharmacological S/E-loss of libido, erectile dysfunction, but rarely gynaecomastia
      • Non-steroidal
        • Pharmacological S/E- gynaecomastia (49–66%), breast pain (40–72%), hot flushes (9–13%)
        • Non-pharmacological S/E related to individual drugs
    • Androgen deprivation is one of the most effective therapies against any solid tumor; unfortunately, with time, almost all prostate cancers will become androgen refractory
  • 83. CHEMOTHERAPY
    • Hormonal Therapy is effective for an average of 2 years
    • Clonal proliferation of androgen insensitive prostate cancer cells over time results in hormone refractory disease
    • Patients may experience new or worsening symptoms, or a consistent elevation of the PSA at some point in the disease course
    • Disease progression in spite of castaration level testosterone termed as Hormone Refractory Prostate Cancer (HRPC)
    • Some patients may respond to 2nd line hormonal therapy
    • Response rates vary from 20-60%
    • Improvement is usually temporary
    • Patients who progress after further hormonal manipulation may be candidates for chemotherapy
    • FDA-approved agents prior to 2004:
      • Mitoxantrone
      • Estramustine
    • Main benefit is improvement in pain with limited objective responses and NO Survival benefit
  • 84. TAX 327
    • 1006 patients in 24 countries with HRPC were randomized to one of three chemotherapy regimens:
      • Docetaxel every 3 weeks (with prednisone)
      • Docetaxel every week (with prednisone)
      • Mitoxantrone every 3 weeks (with prednisone)
    • Patients who received Docetaxel every 3 weeks ( with prednisone ) experienced :
      • Improvement in median survival of 2 months (18.9mvs. 16.5 months)
      • Greater PSA decline (45% vs. 32%)
      • Improvement in Pain (35% vs. 22%)
      • S/E were manageable
    William Berry and Mario Eisenberger -The Oncologist 2005;10(suppl 3):30–39 Charles J. Ryan and Mario Eisenberger - J Clin Oncol 23:8242-8246
  • 85. ADJUNCTIVE T/T
    • Bisphosphonates:
      • Aledronate (Fosamax)
      • Zoledronate (Zometa)
      • Pamidronate (Aredia)
    • Strong affinity for bone
    • Directly inhibit osteoclast activity: prevent bone resorption
    • induce osteoclast apoptosis
    • Zoledronate
      • Indicated for treatment of men with HRPC
      • 4 mg IV q 3 wk
      • Decreases skeletal related events: Bone resorption / pathologic #
      • Decreases bone pain
      • No effect on disease progression, PSA, Survival
    • Rationale
      • Bone resorption increaed in metastasis which contributes to skeletal morbidity
      • ADT further increases bone resorption
  • 86. TARGETED CRYOABLATION OF PROSTATE
    • Cryoablation: cancer treatment by freezing to -40 º Centigrade
    • Immediate cancer cell death
    • Dead cells are slowly reabsorbed by the body
    • Minimally invasive -No surgical incision, minimal blood loss, no radiation
    • OPD procedure, with rapid return to normal activities
    • A well-established treatment for localized prostate cancer
    • ? Better than radiation for high risk (e.g. high GS) disease
    • T/t of recurrence after radiation
    • No increase risk of rectal or bladder cancer
    • No cystitis or proctitis
    • Can be combined with hormonal therapy
    • Can be repeated if necessary
    • More rapid recovery than after RP
    • Erectile dysfunction frequent but treatable
    • Adv - Higher preservation of potency
    • Disadv - No sampling of the tumor
    • and the “fear” of residual cancer not killed
  • 87. PROGNOSTIC FACTORS
    • Grade
    • Stage
    • PSA
    • % biopsy cores
    • PSA velocity
  • 88.  
  • 89. SCREENING GUIDELINES FOR THE EARLY DETECTION OF PROSTATE CANCER (AMERICAN CANCER SOCIETY)
    • PSA test and DRE should be offered annually,
      • Beginning at age 50, to men who have a life expectancy of at least 10 years.
      • Men at high risk (African-American men and men with a strong F/H of one or more first-degree relatives diagnosed with prostate cancer at an early age) should begin testing at age 45.
    • For men at average risk and high risk, information should be provided about what is known and what is uncertain about the benefits and limitations of early detection and treatment of prostate cancer so that they can make an informed decision about testing.
  • 90. Very high : T3b-T4 <10yr >10yr Expectant m/m or RT or RP±PLND RP±PLND or RT Androgen ablation or RT+Androgen ablation Any T, N1 Any T, Any N, M1 Androgen ablation Androgen ablation or RT+Androgen ablation Relapse risk Expected survival Initial T/t LOW : T1, T2a GS 2-6 PSA< 10 <10yr Intermediate : T2b, T2c GS 7 PSA-10-20 Expectant m/m or RT or RP±PLND High : T3a GS 8-10 PSA>20 >10yr Expectant m/m or RT Androgen ablation +RT or RT or RP±PLND
  • 91. THANK YOU
  • 92.  
  • 93.  
  • 94.  
  • 95.  
  • 96.  
  • 97.  
  • 98.  
  • 99.  
  • 100.  
  • 101.  
  • 102.  
  • 103.  
  • 104.  
  • 105.
    • Most widely used system devised for the USA-based Veterans’ Administration Co-operative Urological Research Group (VACURG)
    • Grade 1: well-differentiated carcinoma with uniform gland pattern.
    • Grade 2: well-differentiated carcinoma with glands varying in size and shape.
    • Grade 3: moderately differentiated carcinoma with either (a) irregular acinae often widely separated; or (b) well-defined papillary/cribriform structures. This is the commonest pattern seen in carcinoma of the prostate.
    • Grade 4: poorly differentiated carcinoma with fused glands widely infiltrating the prostatic stroma. Neoplastic cells may grow in cords or sheets and the cytoplasm is clear.
    • Grade 5: very poorly differentiated carcinoma with no or minimal gland formation. Tumour cell masses may have central necrosis.
  • 106.  
  • 107. Targeted Cryoablation of the Prostate (TCAP) Before Probes Placed Prostate frozen
  • 108.  
  • 109.  
  • 110.
    • PTV I
    • PTV II
  • 111. IMRT PLAN SUM
  • 112.  
  • 113.