Carcinoma prostate
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Carcinoma prostate
Dr kiran pJunior resident radiotherapy
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INCIDENCE
• Common in western world• One in six American men will be diagnosed
with prostate cancer during his lifetime• Europe, the annual incidence rates were 214
per 1000 men
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DIAGNOSIS STAGING WORK UP
• DRE• PSA • TRUS • getting a histological confirmation of prostate
cancer
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DIGITAL RECTAL EXAMINATION
• simple, cost effective method• Positive predictive value from 21% to 53%• Good staging method• sensitivity of 52% and specificity of 80%• MAY UNDER/OVER ESTIMATE
J URO 1999;161:835-9
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PROSTATE SPECIFIC ANTIGEN
• The normal PSA are <4 ng/ml• threshold PSA level for detection of cancer is
4.0 ng/ml• BUT 25% will have a normal or low PSA• PSA <10 ng/ml - low risk of peri-prostatic
spread and metastases
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PSA
• PSA >20 ng/ml-An increased risk of peri-prostatic spread, seminal vesicle involvement and distant metastases
• GENERAL RULES• PSA >10 ng/ml indicates capsularpenetration
in more than 50% patients • PSA >50 ng/ml – metastatic disease.
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PSA
• prostate specific • Not cancer specific• BPH, prostatitis, tuberculosis etc• borderline zone of 4-10ng/ml
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FREE TO TOTAL
• < 0.15 -a higher Gleason score ,poorer prognosis
• free to total PSA of <0.1 is most likely• higher percentages with BPH
JAMA 1998;279(19);1542-7
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Prostate biopsy
• Extended biopsy is more preferable• cancer detection rate- 40%,• sextant biopsy -20% to 25%
REV UROLOGY 2007 SUMMER,9(3):93-98
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BIOPSY
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• Sextant biopsies -undersample most and miss many
• Extended biopsies increase detection rates decrease sampling error.
• Initial biopsies should include at least 12 cores from the peripheral zone.
• repeat biopsies - anterior apical biopsies or saturation approaches is recommended.
.REV URO 2007 SUMMER;9(3)::93 98
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CT/MRI
• T1&T2-with probability of LN involvement>10%
• T3-T4
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• DREsize, location, volume, local extension• TRUS/Endorectal coil MRIlocal extension• CT/ProstaScint Scanpre-op pelvic node
assessment• Bone Scanmets
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Bone scan
• MRI superior?• Indication T1+PSA >20 T2+PSA>10 Gleason score >=8 T3&T4
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Predictive models in Ca prostate
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TREATMENT
• NATURAL HISTORY OF PROSTATE CANCER IS DIFFICULT TO PREDICT
• Men with similar stage ,glisson score,psa can have markedly different outcome
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OUTCOME WITH SCREENING
J natl Cancer inst.2009 March 18;101(6)
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high grade prostatic intraepithelialneoplasia (PIN)
• Not an indication for treatment
• careful follow-up, early re-biopsy to rule out invasive cancer
• No evidence at the present for early treatment
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Invasive prostatic adenocarcinoma
• Localized prostate cancer (T1 – T3a N0)
• Locally advanced disease (T3b-T4 N0)
• Metastatic disease: Any T, N+ or Any T, Any N &distant metastasis (M+)
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Localized prostate cancer (T1 – T3a N0)
• Low risk (cT1-T2a and Gleason score 2-6 and PSA< 10)
• Intermediate risk (cT2b-T2c or Gleason score = 7or PSA 10-20)
• • High Risk (cT3a or Gleason score 8-10 or PSA >
20)
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LOW RISK
• Very low risk gleason score-2-6 T1c psa<10ng/ml fewer than 3prostate core biopsies positive <=50% cancer in each core psa density-<0.15ng/ml/gm• Low risk
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Life expectancy -<5yr-any risk
• If asymptomatic –no further work up or treatment
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Very low risk
• Life expectancy -<20yrs-AS• PSA -3MONTHLY• DRE-6MONTHLY• Repeat biopsy-yrly
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Low risk
• cT1-T2a and Gleason score 2-6 and PSA< 1
• Life expectancy<10yr,>10yr
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Life expectancy
<10 yrs
AS
>10 yrs
AS RADICAL RX
SX RT
EBRT
BRACHY
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ACTIVE SURVEILLANCE(AS)
• Most men with good risk prostate cancer have indolent and slow growing disease
• risk posed by cancer can be assessed with some degree of certainty that delayed treatment will be as curative as immediate treatment.
• attempt to avoid over-treatment in the majority of patients
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AS
• low-volume, low-grade carcinoma • elderly patients or medical comorbidities with
limited life expectancy comply for• regular follow up
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AS
• PSA tests and a digital rectal examination every 3 months for 2 years
• repeat biopsy 6-12 months after the initial diagnosis and yearly when indicated
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ASRADICAL RX
• PSA DT of < or = 3 years (based on a minimum of 3 determinations over 6 months) are offered radical intervention.
• re-biopsy score• tumor volume• stage progression • patient preference
urol oncol 2006 jan -feb 24(1) 46-50
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AS
• PSA doubling time• re-biopsy score• , tumor volume• stage progression • patient preference.
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Outcome
• AS- 85% would remain treatment-free at 5 years
• no patient died from prostate cancer.
solowey etal ..BJU INTRN 2008 JAN;101(2) 165-9
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• 65% remained free of treatment at 8 years.
• The prostate cancer specific survival using this approach was 99.3% at 8 years
urol oncol 2006 jan -feb 24(1) 46-50
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Radical prostatectomy
• RP -removal of the entire prostate gland between the urethra and the bladder, with resection of both seminal vesicles
• is recommended for the organ confined prostate cancer with life expectancy of >10 years
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RP
• complete removal of cancer • accurate pathological staging and allows
better planning for adjuvant therapy.
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RP VS AS
j natl cancer inst 2008 aug 20;100(16) 1144-1154
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RP VS AS
j natl cancer inst 2008 aug 20;100(16) 1144-1154
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RP VS AS
j natl cancer inst 2008 aug 20;100(16) 1144-1154
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RP
• Retro pubic• Perineal• Retro pubic-common, enables simultaneous
pelvic lymph node assessment• Robotic assisted-more magnification –reduce
morbidity
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RP
• Low risk• Intermediate-risk Prostate Cancer and a life
expectancy of more than 10 years.
• prognosis -excellent when the tmr is confined to the prostate based on pathological examination
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Pelvic node dissection
• Cut of-6%
• The sensitivity- 87.9%• specificity- 54%• negative predictive values-97.3%• associated with the 6% cut off
int j radtn oncol biol phys 2012 jun;83(2) 624-9
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Pelvic node dissection
• Importance-to determine adjuvant therapy
• Only ePLND
• removal of obturator, external iliac, and hypogastric lymph nodes
int j radtn oncol biol phys 2012 jun;83(2) 624-9
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Pelvic node dissection
• No use <10 nodes• 28 nodesnodes
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RP in high risk prostate
• no consensus regarding the optimal treatment of men with high-risk localized disease
• discouraged,because of increased risk of positive surgical margins and lymph node metastases and/or distant relapse
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NAHT followed by RP
• THEOROTICAL ADVANTAGE
• potentially downstage locally advanced tumors,
• thus making them more amenable achieving negative margins at the time of surgical resection
cochrane database syst rev.2006 octo18;(4):CD006019
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• NHT have shown a significant decrease • in positive surgical margins• and lymph node metastasis, • reductions in tumor size • PSA levels
BUT
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• NO DIFFERENCE IN DESEASE FREE SURVIVAL• OVERALL SURVIVAL
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NAHT followed by RP
• Cochrane review(level of evidence: 1a)
• NAHT before RP does not provide a significant OS advantage over prostatectomy alone
• NAHT before RP does not provide a significant advantage in disease-free survival over prostatectomy alone
cochrane database syst rev.2006 octo18;(4):CD006019
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NAHT before RP does substantially improve
• local pathological variables such as organ-confined rates, pathological down staging, positive surgical margins and rate of lymph node involvement.
• NHT prior to prostatectomy is not recommended
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COMPLICATIONS OF RP
• mortality rate is 0-1.5%
• urinary fistulas are seen in 1.2-4% of patients
• urinary incontinence persists after one year in 7.7%
• Less complications procedure is performed in a high-volume hospital and by a surgeon
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• Erectile dysfunction used to occur in nearly all patients
• nerve-sparing techniques can be applied in early-stage disease
• nerve-sparing RP may have a higher chance of local disease recurrence
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RDIOTHERAPY
• No direct RCT between surgery vs RT• Retrospective analysis not much of difference
between both modalities
• radical&palliative
• EBRT• EBRT+BT• BT
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CONVENTIONAL EBRT
• Patient supine
• Hands over chest
• Immobilization –
• Four field BOX
• Shrinking field technique
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• Superior border-L4-L5-to include the common iliac nodes
• Inferior border-1.5 -2cm below the junction of prostatic and membranous urethra –just below the ischial tuberosities
• Lateral margin-1-2 c from the lateral boney pelvis
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• Anterior -pubic symphysis
• Posterior margin-S2-S3 junction to include the pelvic and presacral nodes+sparing posterior rectal wall
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• Anterior -pubic symphysis
• Posterior margin-S2-S3 junction to include the pelvic and presacral nodes+sparing posterior rectal wall
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Boost field
• Cystogram –• supine ,catheter insitu-20 ml of contrast+10ml
of air introduced into bladder• 20 ml of contrast into catheter balloon which
is pulled down to bladder base• AP film in simulator-2cm margin is given with
bladder base as center
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DOSE
• Conventional-60 to 70gy/1.8-2gy per fraction
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DOSE escalation
• Depends on risk• Low risk-a minimum dose of 70 - 74 Gy is
(external with / without brachytherapy)• Ideal-75-79 GY for low risk• Intermediate &high risk-can extent to 81GY.• (level of evidence : 2)
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Intermediate risk
• minimum dose of 74 - 76 Gy is recommended for Int risk group(level of evidence : 2)
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High risk
• minimum dose of 74 - 80 Gy is recommended for high risk group(level of evidence : 1a)
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• meta-analysis of data obtained exclusively fromRCT’s provides evidence that high dose RT is superior to conventional dose RT in terms of preventing biochemical failure in low-, intermediate-, and high-risk
• high dose RT should be offered to all patients regardless of their risk status
int j Radiat Oncol Biol phys.2009 aug1;74(5):1405-18.
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DOSE
• 70 and 80 Gy• Significant increase in the 5-year Biochemical
control rate• low-14% • Intermediate- 17.8%• high-risk-19.2% (Level of evidence :1a)
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Prophylactic WPRT• RCT -NO benefit from prophylactic irradiation of the pelvic lymph
nodes in high-risk cases (46-50 Gy).
• risk of LN involvement of 15% to 35% -benefited the most from pelvic nodal RT
• less than 15% or
• more than 35%(higher distant metastasis) did not benefit from pelvicnodal RT
• (level of evidence 2b )
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WPRT VS PORT
int j Radiat Oncol Biol Phys.2007.NOVEMBER 1;69(3)646-655
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INTERSTETIAL BRACHYTHERAPY
• Permanent• Temporary
• Permanent-Ideal-are those with favorable risk prognostic features who have a high likelihood of organ-confined disease
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• PSA levels 10ng/mL or less,
• Gleason scores less than 6-7,
• Clinical stages T1b- T2a
• prostate volume of < 50 cm3 and
• good International Prostatic Symptom Score (IPSS)
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International Prostate Symptom Score
• International Prostate Symptom Score (IPSS) is an 8 question (7 symptom questions + 1 quality of life question)
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IPSS result of 7 symptoms questions
Score Correlation[1]
0-7 Mildly symptomatic
8-19 Moderately symptomatic
20-35 Severely symptomatic
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• not recommended for patients with locally advanced disease
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EBRT+BRACHY
• intermediate and highrisk patients with localized prostate cancer
• I 125 seeds or Pd 103• EBRT-45 to 50 Gy - conventional / conformal
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• low-dose-rate boost -dose 90-100 Gy for 103Pd implants
• 110 Gy for 125I implants
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• HDR brachytherapy-trans-perineal placement of after-loading catheters in the prostate under ultrasound guidance.
• CT-based treatment planning• DOSE-4 to 6 Gy –each 24 to 36 hours using192Ir. Followed by EBRTdose of 45 to 50.4 Gy using conventional fractionation
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HDR-advantage
• more easily optimize the delivery of RT to the prostate
• reducing the potential for under-dosage ,• reduces radiation exposure • radiobiologically more efficacious in terms of
tumor cell kill for patients with increased tumor bulk or adverse prognostic features.
.
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EBRT vs EBRT+LDR vs EBRT+HDR
• EBRT+HDR - give better biochemical control& better overall survival as compared to external beam radiotherapy alone.
• biochemical control rates with LDR was comparable to that of HDR
• overall survival was better with HDR brachytherapy.
• (Level of evidence: 1a)
RADIOTHERAPY&ONCOLOGY(2009);VOLUME:93,ISSUE 2
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POST OP RT
• Indication-positive surgical margins, seminal vesicle invasion and/or extracapsular extension
• recommended doses are 60-64Gy• (level of evidence:1)
radiother oncol.2008 jul88(1)
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evidence
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POST OP RT
• Immediate vs late• Immediate postoperative radiotherapy -well
tolerated, with• grade 3-4 urinary toxicity of less than 3.5%
without significant differences regarding the rate of incontinence and/or stricture of anastomosis.
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• immediate post-operative radiotherapy -better
• five-year clinical or biological survival:• Immediate- 72.2% vs 51.8% (p < 0.0001)
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Androgen deprivation therapy
• Clinically localized disease• Neo adjuvant/concomitant/adjuvant-prolongs
survival in radiation managed patients• When ever used cab should use• Indicated in all high risk + locally advanced +
metastatic disease(2-3 yrs)• Short term androgen deprivation in
intermediate risk (4-6 months)
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Adverse effect
• Hot flushes • vasomotor instability• Osteoporosis• Obesity insulin resistance• Greater risk of DM, cardiac diseses
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locally advance Prostate Cancer(T3b-T4)
• Neo-adjuvant hormone therapy followed by Radical radiation therapy
• Neo-adjuvant hormone therapy followed by Radical prostatectomy
• Hormonal therapy alone
• Watchful waiting - Elderly patients with limited life expectancy
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Treatment of Metastatic Disease
• a) Metastatic nodal (N+) disease• b) Distant Metastatic (M+) disease
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Metastatic nodal (N+) disease
Treatment Options include: Hormanet therapy Watchful waiting (WW) Surgery Radiation therapy
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HORMONE THERAPY
• mainstay of treatment -of long term hormonal therapy
• local therapy- with radiation therapy preferred
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Watchful waiting (WW)
• Elderly patients
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Surgery
• Lymph node-positive (N+) disease will mostly be followed by systemic disease progression, and all patients with significant N+ disease will ultimately fail treatment.
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RADIATION THERAPY
• INDICATION• pelvic lymph node involvement lower than the
iliac regional nodes,• younger than 80 years old • WHO performance status 0-1 and• no severe co-morbidity
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• External beam irradiation plus immediate long-term hormonal manipulation-
• (level of evidence : 1b)
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DISTANT METASTATIC DISEASE
• Immediate hormone therapy is indicated
• should be offered early to all patients
• BOTH symptomatic and asymptomatic
• (level of evidence:1).
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• Response rate-85%• median duration of response of 18 months• median survival of 36 months.• median survival of 36 months• ranges between 28 and 53 months• >10 yrs-only 7%
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osseous metastases:
• Surgical intervention-Decompressive surgery in spinal cord compression
• Pathological fracture of weight bearing bones in patients with reasonable life-expectancy
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RADIATION THERAPY
• EBRT-for painful or unstable skeletal metastases
• DOSE -800 CGY –SINGLE fraction(Level of evidence: 1b)
• Fractionated RT for bone metastases may be considered-spinal cord compression
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30/10 vs 800 single
• acute toxicity was more frequent in the 30-Gy arm
30/10-17% 8-Gy arm 10%Late toxicity-rare in both arms & is same 4%-in both arms
J Natl Cancer Inst.2005 jun 1;97(11)
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• overall response• 8-Gy Complete -15% partial response - 50%• 30-Gy Complete- 18% Partial- 48% in the arm
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Hemibody radiation
• Multiple symptomatic skeletal metastases• 8 Gy for UHBI& 6 Gy for LHBI
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Systemic radionuclide therapy
• Strontium89 • Samarium153• improve bone pains in upto 70% patients
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Bisphosphanates
• reduce bone pains • skeletal-related events including fractures• inhibit osteoclast-mediated bone resorption and osteoclast precursors effective-HRPCresponse rate of 70-80%
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• reduce pain • provide total pain relief• Effect more important- HRPC• Decreases pathological fractures-10%• skeletal related events-11%• time to first skeletal-related event-prolonged• Toxicity-osteo necrosis jaw necrosis,
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HORMONAL THERAPY
• Androgen deprivation- suppressing the secretion of testicular androgens –
surgical medical castration
• Anti-androgens -inhibiting the action of the circulating androgens at the level of their receptor in prostate cells
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• When two modalities can be combined- complete (or maximal or total) androgen blockade (CAB).
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b/l orchidectomy
• Simple&quickest way to achieve a castration level
• Usually- obtained in less than 12 hours• main drawback- negative psychological effect
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Long acting LHRH agonist
• Currently the predominant forms of ADT• Synthetic analogues of LHRH• interfere with the hypothalamic-pituitary-
gonadal axis• initially stimulate pituitary LHRH receptors
• inducing a transient rise in LH and FSH release
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• consequently elevate testosterone • testosterone surge or ‘flare up’ phenomenon• begins 2-3 days of first injection and lasts
through first week• comparable efficacy to orchiectomy (level of
evidence: 1a)• Currently standard of care in hormonal
therapy
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• detrimental effects- flare phenomenon increased bone pain, acute bladder outlet obstruction,obstructive renal failure, spinal cord compression
• fatal cardiovascular events due to hyper-coagulation status
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Anti androgens
• compete with testosterone and DHT for binding sites on their receptors in the prostate cell nucleus
• promoting apoptosis and inhibiting Prostate Cancer growth
• Steroidal& non steroidal• Both competes with androgen at receptor but
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• steroidal anti-androgens additional progestational properties with central inhibition of the pituitary gland
• M1 patients, an improvement in OS with castration
• M0 patients no significant difference in OS
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Intermittent Vs Continuous Androgen Deprivation
• long-term CAB- which stimulates prostate cell apoptosis
• fails to eliminate the entire malignant cell population
• after a variable period-tumor invariably relapse- averaging 24 months
• Androgenindependent state of growth
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Androgen-independent progression
• begin early after the administration of HT• Coinciding with the cessation of androgen-
induced differentiation of stem cells• cyclical ADT can make a clone –still
sussceptable to ADT
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Biochemical relapse after local therapy
• RP- undetectable within 3 weeks• Persistently elevated PSA- PSA-producing
tissue remains in the body• rapidly increasing PSA level- distant
metastases(first 2yrs)• slowly increasing-local reccurrence• two consecutive values of 0.2 ng/mL or
greater
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• RARELY-undifferentiated tumors- local treatment failure and distant metastases-undetectable PSA levels
• 50%-50%-local failure-distant mets
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RADIATION THERAPY
• PSA nadir of less than 0.5 ng/mL• Interval for nadir varying some times very
long-3yrs• biochemical failure-Rising PSA->2ng/ml-above
nadir psa• Three consecutive PSA rises• late and slowly rising PSA is a sign of local
failure
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LOCAL RECCURRENCE
• prostatic biopsy demonstrating malignant cells18 months or longer after initial radiotherapy
• PLUS associated psa elvation• No mets detected-MRI,CT,BONE SCAN
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HRPC-hormone refractory prostate cancer
• Serum castration levels of testosterone (< 50 ng/dL, or < 1.7 nmol/L)
• 3 consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA > 2 ng/mL
• PSA progression, despite secondary hormonal manipulations
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management
• anti-androgen withdrawal• addition of ant androgens• anti-androgen replacement• estrogenic compounds,• adrenolytic agents
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• 1/3 will respond to anti androgen withdrawal > 50% PSA decrease in 4 moths
• flutamide was replaced by bicalutamide and vice versa
• Aminoglutethimide, ketoconazole and corticosteroids-also have some role with –anti androgen therapy
• DES-20-80% response rate but more complication
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Cytotoxic chemotherapy
• Docetaxel containing CT-progress within 6 to8 months
• So toxicity should balanced with benefit
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ROLE OF RT
• Conventional-four field box f/b boost to prostate and seminal vessicle-but rectal and bladder toxicities more
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• 3 Dimensional Conformal techniques.• Multi-leaf collimators to “shape” fields• Reduced toxicities but no selective “sparing”
possible
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Intensity modulated Radiotherapy
• Multiple non-coplanar beams ->• Inverse planning -> different • intensities -> highly conformal dose• distribution with normal tissue• sparing.
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Image Guided RT (IGRT)
• EPID, USG with Fiducial markers etc• Recently , CBCT-kV or MV , • Tomotherapy ,Cyberknife etc
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Conformal RT
• 3DCRTIMRT boost /IMRT alone
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Respiratory motion
• Superior –inferior-2.9+/-1.7• Anterior-posterior-1.6+/-1.1
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• ABS :monotherapy :T1c-T2a, GS<7,PSA≤10• + EBRT : T≥2c, GS ≥7, PSA >10• C/I :metastases, gross seminal vesicle J• involvement, large T3 disease.
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Permanent seed implants
• IODINE(I 125) & PALLADIUM (Pd 103 )• Preplanned Transperineal • Implantation (Seattle Method)• TRUS guided• Intra-operative Planning Techniques• TRUS guided needle placement f/b intra-op • CT/MRI >Contouring > optimization > seeds.• LDR DOSE• Monotherapy : I-125 144 Gy; Pd-103 125 Gy.• After 40–50 Gy EBRT: I-125 110 Gy; Pd-103 90 Gy.
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HDR-BRACHY
• After loading catheters under trus guidence• I192• After EBRT-9.5 GY-two fractions• Monotherapy-9.5GY bid X 2 days 10.5 gy X 3
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LDR BRACHYTHERAPYHDR BRACHYTHERAPY
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RT in Combined Approach• Surgery + Adjuvant RT (Ind: ECE ,Margin+ or SVI)• SWOG 8794 : 431pts: Observation Vs. RT 60- 64Gy• 15yr OS:38->46%,bF:77->55%,LF:22%->8%.• QOL worse initially , later better.
• EORTC 22911 : 1005 pts : Obsn Vs. RT 60Gy• 5yr OS: No diff,bPFS:5374%,LRF: 15 5%,• No significant diff in toxicities-02
• Salvage RT after RP: beneficial if PSA-DT< 6-10month• LN-,lower pre-RT PSA,GS<8.• Increases Prostate cancer Specific Survival.•
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• RT + short term HT (STHT)• 3-6 months of HT improves bPFS by 15-25% and CSS by 3-
8% Vs. No HT.• TTROG(Denha et al.2005),Crook et al.( 2004),RTOG
9413, Lavadiere et al• D’Amico et al and RTOG 8610 trials showed 10-15% OS
benefit.• RT + long term HT• For high risk patients, HT for >2-3 yrs improves OS by
10-15% ,CSS by 5% and DFS by 20-30% Vs. no HT or 4-6 month HT.
• (RTOG 8531,EORTC 22863,RTOG 9202,EORTC 22961)•
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• PSA & DRE :every 6 months for 5yrs,then annually.• PSA FAILURE• Phoenix definition : current ASTRO/RTOG• EBRT with/without short term HT• - a rise by ≥2 ng/mL above the nadir PSA.
• PSA nadir : After RP : 3 weeks• EBRT:2-3yrs• Brachytherapy : 3-4 yrs• PSA bounce : transient PSA rises(<2ng/ml)• EBRT & Brachytherapy:20%• (9-14mnths)
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Treatment related toxicities
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• Late toxicities :• Urinary stricture : <4 %• If prior TURP/prostatectomy • 4-9 % stricture/stress incontinence• Post treatment Impotence :• Brachy (24%),EBRT + Brachy (40%),EBRT alone(45%), Nerve Sparing
RP(66%), Non Nerve sparing RP (75%).• Robinson JW et al. Int J Radiat Oncol Biol Phys
2002;54:1063-1068.• Perioperative complications : Obstructive symptoms (10%), Urinary
incontinence (1-3%),rectal injury (1-5%)
• Second cancers :(SEER, Tward 2008) No significant difference ,• RP Vs. EBRT
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Future directions
• Dose escalation • 70.2 Gy Vs. 79.2Gy :T1b-T2b,High dose less likely to have
local failure , HR=.57, 10yr BF: 32.4% Vs. 16% in high dose. Zietman et al JCO 2010 Mar 1;28(7):1106-11
• Proton Therapy
• Molecular agents & New chemotherapy agents
• Immunotherapy Sipuleucel-T-relative reduction of 22% in the risk of death NEJM 2010 Jul 29;363(5):411-22
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summery
• Role of Radiotherapy in Ca Prostate is time-tested.
• All stages and risk groups are benefitted with RT.
• In future , Radiobiology research , Molecular Pathways and Technological innovations are the keys to enhance the treatment.
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Thank you