Academic Discussion on the management of Prostate cancer by Dr. Abhishek Basu (MD, DNB) for Radiation oncology & Medical oncology residents.

1. MANAGEMENTOF PROSTATECANCER:
CONTEMPORARYGUIDELINES & FUTURE DIRECTIONS
DR. ABHISHEK BASU
CLINICAL TUTOR, MCH
KOLKATA, SEPT 2020

2. Pictures tell a thousand story…

3. THE PROSTATE PYRAMID
Must Know
Should Know
Nice To Know

4. EPIDEMIOLOGY
• Sixth leading cause of cancer death among men worldwide, 2nd MC in US.
• The worldwide burden is expected to grow to 1.7 million new cases and
499,000 new deaths by 2030 simply due to the growth and aging of the global
population.
Estimated incidence in India (2020) is 41,532 with CR 5.7 & cum risk 1 in
125. It is not among top 5 common cancer in male (Cancer
Registry2020,ASCO/GLOBOCAN)
Risk Factor: Increasing age
Ethnic origin (African- Americans)
Heredity
- 1st degree relatives diagnosed below the age of 60
- BRCA 2 mutation
- Lynch Syndrome

5. CLINICAL ANATOMY

6. PATHOPHYSIOLOGY

7. GnRH

8. GLEASON SCORING

10. WHAT DOES THE GRADE OF THE TUMOR
PREDICT?
Grade of a tumor is predictive of its likelihood to spread
beyond confines of the prostate, affecting curability.
12% of low-grade tumors (2-4) spread beyond
prostate in 10 years.
33% of medium-grade tumors (5,6) spread
beyond prostate in10 years.
61% of high-grade tumors (7-10) spread
beyond prostate in 10 years.
Sources:Mayo Clinic.com.ProstateCancerGuide.Available at: http://www.mayoclinic.com/health/prostate-
cancer/PC99999. ProstateCancer in California.Ed. Mill PK. PublicHealthInstitute. 2000.

11. GLEASON GRADING
Prostate
Cancer
Gleason Score
Risk of
death in
15 years
2 - 4 4 - 7 %
5 6 - 11%
6 18 - 30%
7 42 - 70%
8 - 10 60 - 87%
Albertson PC, et al. JAMA 1995; 274: 626-
631

12. PROSTATE SPECIFIC ANTIGEN (PSA)
• Protein produced by glandular tissue of prostate
• Present in small but measurable quantities in
normal, healthy men
– “normal” range increases with age
• Elevated PSA suggests
– Benign hypertrophy
– Recent ejaculation
– Prostatitis/infection
– Prostate cancer

13. PROSTATE SPECIFIC ANTIGEN (PSA)
• Normal Range 0-4ng/ml
• Age specific
PSA
Age
(years
)
Recommended Reference
Range for Serum PSA
(ng/mL)
40–
49
50–
59
60–
69
70–
79
0.0–
2.5
0.0–
3.5
0.0–
4.5
0.0–
6.5.

14. PROSTATE SPECIFIC ANTIGEN (PSA)
• PSA > 4 ng/ml ? Always Cancer.
• PSA 4 – 10 ng/ml 25% will have Prostate ca.
• PSA > 10 ng/ml 50% will have Prostate ca.
Free and total prostate-specific antigen:
Less than 10%
Biopsy indicated

15. SOME MUST KNOW DEFINITIONS
1. Free PSA – unbound PSA floating freely in the blood stream. Level of free PSA
< 25% - increased risk for CA, more free PSA- benign
2. PSA density- (PSA/Gland volume) > 7% = ↑ Risk
3. PSA velocity – ≥2ng/ml/yr is poor prognostic, more chance of GS7+
4. PSA Failure – After RP : > 0.2ng/ml rise with 2nd confirmatory level detected at
≥ 0.2ng/ml. NCCN 2020 says : failure of PSA to fall undetectable levels
(persistence) or undetectable PSA becomes detectable on 2 or more occasions
then its PSA recurrence.
2005 Phoenix definition: nadir + 2 ng/ml post EBRT
5. Adjuvant RT- when undetectable post op PSA (German ARO 96-02)
6. (Early)Salvage RT- detectable post RP PSA( SWOG 8794, EORTC 22911)
7. CRPC – clinical/radiological/biochemical progression despite castrate level of Sr
testosterone (< 50ng/dl)

16. PROSTATE PEARLS…QUIZ SPECIAL
1. Prostate Health Index( PHI) – clinical aid for PSA (4-10)
PHI= [-2]Pro PSA/ Free PSA ×√PSA
Score % Chance of CA
0-23 8.7
23-45 20.6
45+ 40-45
2. 4K score – Total PSA, free PSA, intact PSA, Human Kallikrein factor2
3. Urine Biomarker for ca prostate – TMPRSS2 – ERG fusion
4. Genomic Marker : Favorable - FGFR3 mutation positive
Unfavorable – compound loss of PTEN + RB1
5. Role of ADT discovery – Charles Huggins
6. HOLEP : Holmium laser enucleation of prostate. ( ≥ TURP in BPH)

17. REMEMBER THE LQ MODEL ??
α (alpha) = initial slope; intrinsic
Radiosensitivity, linearly dependent.
β (beta) = “curviness” ?repairable injury,
proportional to the square of dose.
Overall shape depends on both factors.
The α/β ratio thus determines sensitivity
of a cell to alterations in fraction size.
In general:
Rapidly proliferating cells are not very
sensitive to fraction size (high α/β).
Slowly proliferating cells are very
sensitive to fraction size (low α/β).

18. RADIOBIOLOGY OF PROSTATE
α/β = Dose at which linear and quadratic components of cell kill are equal
↑α/β : Cell damage is function of total dose
(Rapidly dividing cells)
↓ α/β : Cell damage is function of dose / fraction.
• If α/β < normal tissue
– Hypofraction has an advantage
• If α/β > normal tissue
– Hypofraction has a disadvantage
• Moderate Hypofractionation—<35 fractions
• Extreme Hypofractionation—<5 fractions
α/β of Prostate = 1.5 (based on published literature)
Brenner IJROBP,1999

21. GLEASON 7 -10
Hypoxia
Higher Androgen Activity
Patients with higher Gleason Score Treated with HT and RT will have
better outcome

22. WHO IS AT RISK?

23. NCCN RISK STRATIFICATION

24. WORK UP

26. DRE
TRUS –guided 6-12 core Biopsy : GS, # Cores, % of core involvement.
Lab: PSA, Testosterone , LFT ( if giving ADT)
Imaging:
USG – TRUS for biopsy and during needle insertion during brachy.
CT – for pelvis &/or abdominal examination for initial workup.
MRI- T staging, TVD, FU scan during PSA failure.
mpMRI ( multi parametric MRI) = T2W MRI + DWI+ DCE
Requires 3 T magnet and no coil. Helps to detect large &
poorly diff cancers( GG≥2). It has been incorporated in TRUS –MRI
fusion guided biopsy for more accuracy.
Detect extra capsular extension, helps in inform decision making
regarding nerve sparing surgery. Equivalent to CT for staging pelvic
nodes.
Finally, mpMRI outperforms bone scan & xray to detect bone mets.
Both sensitivity ,specificity 98-100%.

29. NUCLEAR IMAGING
Tc99m MDP Whole body Bone scan: Intermediate& high/very high risk pts.
Baseline evaluation as well as in PSA failure. Also helpful in monitoring metastatic
cancer to determine clinical benefit of systemic therapy.
18F –FDG PET scan : High risk pts, but not routinely recommended for staging
(NCCN 2020). PET changes treatment options but may not change disease outcome.
PSMA PET scan: PSMA is a type II trans membrane glycoprotein, highly expressed
in almost all PCa cells, with only 5-10% of primary PCa not having PSMA
expression. Isotopes used: 68Ga, 18F.
PSMA PET positivity has been shown to increase with higher tumor stage and grade,
higher PSA levels and doubled time.
Decidedly superior to MRI in terms of identifying distant metastases in patients with
intermediate to high-risk Pca.
Better detection of recurrence (30-40%)at lower PSA level (0.5ng/dl) . Sensitivity 76-
86%, specificity 86%-100%.
Recent FDA cleared radioisotopes for Prostate cancer: C11- Choline, F18-NaF,
F18 fluciclovine.

31. SCREENING – DOES ANY HELP?

33. CONCLUSION
USPSTF (2012) recommends against screening.
AUA (2013) Only in Age grp 55-69 years – shared decision making.
NCCN (2020) - All recommendations are Cat 2A( Based on low level
evidence), even if early detection is made, those patients are put on active
surveillance.
Conflicting results from Randomized trials, no National guidelines.

34. HOW TO PROCEED NOW?

35. VERY LOW RISK
Life Expectancy Options
< 10years Observation
10to 20years Active Surveillance
> 20 years Active Surveillance
RT
Surgery

36. AS= VLR( life exp > 20 yr),LR (> 10 yr). On progression changes to curative
treatment.
Observation- life exp < 10 yrs, on progression to palliative ADT.
Progression- GG 4/5 on repeated Bx, ca is found in greater no of cores of
prostate Bx

37. LOW RISK
Life Expectancy Options
< 10years Observation
> 10years Active Surveillance
RT
Surgery

38. INTERMEDIATE RISK
Life Expectancy Initial Therapy Adjuvant Therapy
< 10years Observation
RT ADT (shortcourse)
> 10years RT ADT (shortcourse)
Surgery RTif adverse
features ADT if
LN positive

39. HIGH RISK
Initial Therapy Adjuvant Therapy
RT ADT (longcourse)
Surgery RTif adversefeatures
ADT (long course) if LN positive

40. VERY HIGH RISK
Initial Therapy Adjuvant Therapy
RT ADT (longcourse)
Surgery RTif adversefeatures
ADT (long course) if LN positive
Treat like metastatic disease,
with ADT alone (selected
patients)

41. MANAGEMENT PARADIGMS
EVOLUTION TO REVOLUTION

42. Manual
Marking
2-D
Image
based
plannin
g
3D-
CRT
IMRT IGRT
IG
Adaptive
RT
2-D Era
3-D Era
4-D Era
EVOLUTION OF EBRT TECHNIQUES

43. ADT TIMELINE
• 1940’s : Surgical removal of testes / exogenous estrogen
• 1945’s : Surgical Adrenelectomy following disease progression
• 1980’s : Non steroidal Anti androgens
• 1980’s : LHRH agonists
• 1990’s : Combined Androgen Blockade era
• 2004 : Docetaxel
• 2010 : Cabazitaxel, Sipuleucel-T, Radium-223, Denosumab
Abiraterone Acetate, Enzalutamide

44. ROLE OFSURGERY
Radical Prostatectomy – curative option for patients having life
expectancy > 10 years and without major comorbidities.
Salvage Radical Prostatectomy- local recurrences after EBRT, Brachy
without any distant mets.
Pelvic LND : for node positive disease, high risk prostate cancer.
Extended PLND includes removal of all nodes from an area bounded by
ext illiac vein anteriorly,floor of the pelvis posteriorly, bladder wall
medially and pelvic sidewall laterally.

45. ROLE OFRADIOTHERAPY
Definitive/ Radical RT – For very low risk life exp > 20 yrs, low risk >
10 years and all others except distant Mets.
Adjuvant RT : pT3 , Margin+.
Half life of PSA 2-3 days, so must wait 1 month before PSA will be
undetectable post-RP.
Salvage RT – Already discussed.
Brachytherapy : to boost the tumor bed dose. C/I to Brachy are:
TURP defect, >60cc or less than 20cc volume of prostate, large median
lobe, pubic arch interference, IPSS > 20, anesthesia risk, prior RT
SBRT: Emerging data, using ultra hypofractionation.
M1 disease (oligometastatic) – Stampede, HORRAD Trial.

46. THE CONUNDRUM OFWHOLE PELVIS RT
Insufficient evidence for elective WPRT in IR & HR Ca Prostate.
Based on RTOG 9413 & GETUG -01. Systematic Review by Piet Dirix
(2014, the green journal) also opined the same, no PFS advantage.
WPRT can be considered in very high risk of LNI or positive SNs.

47. 2D RADIOTHERAPY FIELD
AP/PA- Sup: L5-S1 interface.
Inf: 2 cm distal to membranous urethra.
Lat: 2cm lateral to pelvic brim.
(4corner block) to reduce B&B toxicity
Lateral Field-
Ant: Ant most aspect of sym Pub
Post: S3-S3 interspace.

48. PATIENTPREPARATION FOR SIMULATION

49. RT VOLUMES & TECHNIQUES

50. POST OPERATIVE VOLUMES

51. HYPOFRACTIONATION
PMH / PROFIT 60.0 at 3.0 Gy vs 78.0 at 2.0 Gy [ With out ADT]
RTOG 0415 70.0 at 2.5 Gy vs 73.8 at 1.8 Gy
CHHiP(UK) 60.0 at 3.0 Gy vs 74.0 at 2.0 Gy [ used ADT]
MDACC (ASTRO 2016) 72Gy @ 2.4Gy Vs 75.6 @ 1.8 Gy
HYPRO (DUTCH) trial was negative one @3.4Gy to 64.6Gy – more late
GU toxicity.
MODERATE HYPOFRACTIONATION is safe and effective in radical as
well as salvage settings.
biochemical RFS is improved, no added toxicity, most of the trials were non
inferiority design.
Seminal vessels involved cases are also safely incorporated.
IMRT with IGRT is a mandatory prerequisite for Hypo# RT.

52. EVIDENCE FOR SAFETY IN UFRT/ SBRT

53. KEEP THINGS SIMPLE
Volume Low risk Intermediate
Risk
High Risk Node Positive
CTV 60/74
60Gy/20#
74Gy/37#
Entire
prostate
Entire prostate +
prox 1.4 cm of
SV
Entire Prostate +
entire seminal
(2.2cm) vesicle
Entire Prostate
+ entire seminal
vesicle (2.2cm)
CTV 36.25
7.25Gy/#
weekly(SBRT)
√ √ √ √
CTV 72
Adj RT, 72/36#
× ± boost to
residual
± boost to residual ± boost to
residual
CTV 44(Hypo)
CTV45 ( CFRT)
CTV25(SBRT)
× ×
Peri-prostatic,
presacral,obturator,
internal & external
iliac.
Start from
bifurc of aorta,
ends at sup
border of
symphysis pub.
PORT CTV54
in 20#
× × × √ same as above

54. BRACHYTHERAPY ISOTOPES AND DOSES

55. PROCEDURE

56. SLIDE COURTESY PROF. D.N SHARMA(AIIMS, NEW DELHI )
GTV = TRUS + Baseline MRI
based tumour volume
CTV= Entire prostate + 0.3cm ±
ECE.
PTV= CTV

57. SEED BRACHYTHERAPY/ PERMANENTIMPLANTATION

58. STEPS:
Planning-TRUS guided volume study—computer preplan
Brachytherapy procedure-TRUS guided trans perineal needle-..
peripheral loading..
seeds placed along the tract from base to apex.( No of seeds depends on
volume).
Post implant evaluation- within 60days (ABS)by CT scan Pelvis, CXR (F/U).

59. ADVERSE EFFECT PROFILES….
Surgery has worst incontinence & impotence.
EBRT has worst bowel/ rectal irritation. Commonly acute A/E are dysuria,
fatigue, rectal urgency & diarrhoea/cramping ( if pelvic RT).
Late effects : Radiation cystitis, Radiation Proctitis, urethral stricture, fistula
etc.
Brachytherapy has worst urinary irritation / obstruction but preserves sexual
quality of life.
Placement of rectal spacer can reduce the rectal dose from EBRT.

60. METASTATIC DISEASE – KEYPOINTS
1.In men with metastatic disease, prostate cancer becomes castrate resistant
within 16 months, whereas in non mets case it may be as long as 10 years.
(Gunderson,2020).
2. Local RT is beneficial in only oligomets (< 4) disease , PFS ↑ OS ?
3. ADT requirement is ideally life long- hence B/L orchiectomy is preferred,
if still going for LHRHa – use intermittent vs continuous ADT.
4. Novel anti androgens are tried for CAB.
5. Bone directed therapy and pall RT is advocated for painful skeletal Mets.

61. METASTATIC PROSTATE CANCER

63. FOLLOW UP

64. LANDMARK TRIALS
SL Trial Objective Result
1. ProtecT AS vs RT vs Surgery in low risk Equivocal, 53% of AS
underwent RT/ Sx by 10 yr.
2. PROFIT Hypo#, 60Gy/20# vs 78Gy/39# Non inferior
3. RTOG 0415 Hypo#, 70Gy/28# vs 73.8Gy/41# Non inferior
4. CHHiP ( UK) Hypo#, 60/20 vs 74/37 Non inferior
5. Hypo-RT-PC Ultra Hypo#, 42.7Gy/7# Safe & equivocal.
6. PACE-B SABR Vs IMRT in Localised Dz 36.25Gy/5# is safe
7. PROSPER Enzalutamide in CRPC Improves PFS
8. ALLIANCE Enzalu ± Abiratarone in mCRPC Negative trail, no added Role
9. RAVES/RADICALS Timing of RT after surgery No diff in adj vs eSRT
10. SPARTAN Apalutamide in non mets CRPC Improves PFS
11. LATITUDE Abiratrone + pred in HSPC Improves DFS, OS
12. ORIOLE SABR in Oligo Mets ,48Gy/3-5# Halts Dz progression
13. CHARTED Role of Doce in Mx of mHSPC Doce ↑PFS over ADT alone
14. STAMPEDE 11 arm trial in metastatic CAP Abira,Doce↑, RT ?

65. FUTURE DIRECTION
1. Particle beam therapy ; Proton & carbon beam therapy.
2. Ultra-hypofractionation. SBPT possibly with immunotherapy.
3. Genetic & molecular testing (oncotype Dx, decipher ) for better risk
classification.
4. Incorporation of newer systemic therapy ( abiratarone,
enzalutamide, immunotherapy etc) .

66. TAKE HOME MESSAGE
1. Moderate hypofractionated RT is safe & current Std of care.
2. ADT myths demystified :
 Can be given NAHT, Concurrently & adjuvant ( post definitive RT)
 No role of using neo adjuvant before surgery (RP)
 Generally not given post op unless node positive.
 Duration- 4-6 months (IR), 2-3Yrs (HR,VHR, N+), 6-24months post OP.
 Ideally life long in M1, Surgical castration / intermittent ADT is preferred.
 Can be given with salvage RT if pre salvage PSA ≤ 4ng/ml.
3. M1 – if HSPC – Orchidectomy / LHRHa ± pall RT.
if CRPC – Docetaxel + pred, Abiratarone, enzalutamide etc ± pall RT.

67. THANKYOU….

68. CASE DISCUSSION
1. A 68-year-old man is diagnosed with adenocarcinoma of the prostate
on the basis of a first-time screening PSA of 12 ng/mL. Biopsy shows 7
of 12 cores involved (2 with Gleason 4 + 3, 2 with Gleason 3 + 4, and 3
with Gleason 3 + 3). He has clinical T1c disease. He has a history of
well-controlled coronary artery disease with myocardial infarction over 5
years ago treated by percutaneous intervention. How will you manage?

69. 2. A 62-year-old man undergoes a robotic-assisted radical prostatectomy
for adenocarcinoma of the prostate that was diagnosed after a screening
PSA of 14. The disease is of pathologic stage T3aN0, with 12 lymph
nodes (LNs) dissected, negative surgical margins, and Gleason 4 + 3
disease involving 20% of the gland. His PSA initially falls to
undetectable (less than 0.05 ng/mL), but 1 year later it is 0.11 ng/mL,
and now, 1½ years after his prostatectomy, it is 0.22 ng/mL.
Will you cover nodes in CTV? Will you give ADT concurrently? What
will be the RT Dose? What will be the duration of ADT?

70. CASE 3: IDENTIFY THE STAGE & OUTLINE MANAGEMENT. GS- 4+ 3, PSA– 42.4
BARBOSA, Felipe de Galiza et al. Clinical perspectives of PSMA PET/MRI for prostate cancer. Clinics [online]