Locally advanced Ca prostate Courtesy : NCCN , Perez, Gunderson and Tepper Brief outline on management ADT, Radiotherapy, Surgery indications and Standard of care

1. Dr Sasikumar Sambasivam
DNB Resident
Dept. of Radiation Oncology

2. Locally advanced disease
include clinical stages T3 ,T4
and bulky T2 c tumors.
Options : ADT, RT, Surgery

4. Reducing intracellular concentrations of dihydrotestosterone through
the use of androgen deprivation can induce apoptotic regression of
androgen-responsive prostate cancers
Could help to reduce the primary tumor volume
(i.e.,cytoreductive therapy), which could improve local control and,
therefore, decrease metastatic disease

5. RTOG 83-07 (megestrol and diethylstilbestrol with RT in a phase II
randomized study) --- Both the megestrol and DES in addition to
RT resulted in a high likelihood of clearance of the primary tumor
(94% to 97%) and local regional tumor control (93% and 94%).
Unfortunately, there were significant side effects especially in regard
to the DES (i.e., cardiovascular events).
LHRH agonists and nonsteroidal antiandrogens

6. RTOG study 85-19, which utilized these agents for patients with locally
advanced disease, found them to be well tolerated and resulted in a
high rate of tumor clearance (100%)
RTOG and EORTC Trials
These trials addressed two questions with regard to the use of
androgen suppression and RT (i.e., the roles of adjuvant and
neoadjuvant androgen deprivation)

7. TAS= Flutamide 250 mg tds Goserelin monthly x 4 m

8. RTOG 92-02
OS benefit was observed in patients with
Gleason score 8 to 10
(Along with RT)

9. Hot flashes(50-80 %), sexual dysfunction (universal), gynaco mastia (20%)
and decreased libido(universal) owing to the decrease in testosterone.
In addition, with longer duration LHRH therapy, patients can develop
increased fat mass, decreased lean body mass, and increased waist
circumference.
Understanding the concerns about weight gain and resultant health
issues such as diabetes and cardiovascular disease, several authors have
looked at the large randomized trials to understand whether there is truly an
increase risk of fatal cardiovascular events with RT and LHRH therapy.

10. ? Life threatening complications
RTOG 85-31 and 86-10, EORTC did not report any such events in both
the arms
EORTC 22961 and RTOG 92-02 showed no difference in the risk of CVS
events in short term or long term ADT.
Some authors have challenged these results with a follow up of 12
months
Increased S/c fat
Increased HDL
Increased adiponectin levels
No change in CRP
Insulin sensitivity
Which is different from Metabolic syndrome

11. But LHRHs donot appear to cause these met changes
Caution in patients with obesity and pre existing CVS diseases
Most important : Loss of BMD and a baseline DEXA scan before ADT with
prophylaxis
National Osteoporosis Guidelines recommend Calcium and Vit D3 Supplements
for all men > 50 yrs on ADT
FRAX tool (WHO) to assess risk of fractures
Denosumab (60 mg s/c every 6 m) or Zoledronic acid 5mg IV annually or
alendronate 70 mg P/o weekly increase the BMD during ADT ( when the absolute
fracture risk warrants drug therapy)

15. Antiandrogens :
Bicalutamide 50 mg P/o
Flutamide 250 mg P/o
Nilutamide 300 mg d1-d28 f/b 150 mg as maint.
Abiraterone
Estrogens : fosfestrol (hormone refractory)
GnRH antagonists :
Degarelix 240 mg S/c stat then 80 mg S/c every 28 days
LHRH analogues :
Goserelin 10.8 mg s/c 3 monthly or 3.6 mg S/c monthly
Leuprolide 7.5 mg IM monthly or 22.5 mg 3 monthly or 30 mg 4 monthly

16. Treatment volumes for locally advanced prostate cancer have included
the prostate and seminal vesicles plus a margin along with the
pelvic lymph nodes.
All the large randomized trials have treated the involved tissues in
this fashion using doses to the lymph nodes of 45 to 50 Gy (four-field
box technique and dose prescribed to isocenter) with a boost to
the prostate totaling approximately 70 Gy (isocenter dose)
?benefit from dose escalation for these patients
? Treatment of pelvic nodes a must

17. RTOG 94-13
1323 patients , randomized into three groups
WPRT versus prostate-only EBRT (PORT) and neoadjuvant 4 months
of total androgen suppression versus adjuvant 4 months of total
androgen suppression
No difference in WPRT versus PORT and no statistical difference
between neoadjuvant total androgen suppression versus adjuvant
total androgen suppression

18. Showed an unexpected interaction between the timing of the total
androgen suppression and the extent of the EBRT field.
Progression-free survival was better in the WPRT and neoadjuvant
total androgen suppression study arm versus the other three
groups.
However, this trial was unable to answer, in a definitive way, the
WPRT versus PORT question because of the unexpected interactions.
Therefore the question of WPRT versus PORT still needs to be evaluated
in a prospective trial
Till then the Standard of care would be NAHT+WPRT --- Adj ADT 2-3 yrs.

19. ? benefit was solely due to ADT and not RT
SPCG-7 & SFUO-3 (Phase III RCTs)
875 patients (Scandinavian)
TAS for 3 months followed by androgen deprivation with flutamide
indefinitely versus the same androgen deprivation plus EBRT.
EBRT statistically increased the 10-year prostate CSS compared with the
androgen deprivation alone study arm and statistically increased OS
with very acceptable toxicity rates.(Overall mortality rate at 10 y 39.4 % for
ADT vs 19.6 % for RT and HT arm)
Similar study by NCI Canada (life long ADT vs ADT + RT; 1205 pts; CSM was
23% vs 15% at 10 y )

20. External beam RT
Positioning : RCT : In the supine position, prostate movements during
normal breathing were less than 1 mm in all directions. Hence it is
preferred.
CT simulation in full bladder and empty rectum
Mild laxatives and diet modification during planning and treatment
MRI whenever feasible. CT overestimates prostate volume by 5%

21. Primary Therapy :
Clinical Target Volume :
Pretherapy tumour related factors
Extra prostatic extension , Seminal Vesicle Inv.
Predictive nomograms and risk factors decide whether adjacent normal
tissue should be included in the CTV
The average radial EPE distance from the capsule was 0.8mm in a study (
Davis et al.)
Elective Nodal Irradiation when the risk of LNI reaches or exceeds 15 %
ENI : to include the obturator , internal and external iliac lymphnodes

22. Planning Target Volume:
Setup errors, organ movements , bladder and bowel volumes leading to target miss
Monitoring can be done in many ways (USG, CBCT , implanted fiducials, implanted
electro magnetic transponders)
Range of PTV 0.5 to 1 cm
With out setup correction margin of 11 to 15mm
With daily imaging – 8mm to 13mm
With implanted fiducial markers – 3 mm – 8mm (around prostate and seminal
vesicles)
Using an endorectal balloon daily may position the gland (air redices the rectal
surface dose with buildup at the air and soft tissue interface)

23. 2 D planning :
(1) superior: L5-S1 interspace;
(2) inferior: bottom of ischial tuberosities;
(3) lateral: 2 cm lateral to pelvic inlet;
(4) anterior: approximately 1 cm anterior to
the anterior projection of the pubic symphysis;
and
(5) posterior: S3-4 interspace.

24. Prostate
and
Seminal
Vesicles

25. Contouring
of Prostate
and Seminal
Vesicles

26. Contouring of
Prostate and
Seminal
Vesicles
Contnd..

27. Pelvic LNs

28. Contouring
of Pelvic
nodes

29. Contouring
of Pelvic
nodes
Contind…

30. 3 D CRT or IMRT ( Preferred) ; IGRT in case if Dose prescription > 78 Gy
Doses upto 81 Gy provide improved Biochemical control
LNI is a must in high risk and locally advanced cases
Treatment results appear better when disease burden is lower.
Therefore RT should be started before PSA exceeds 0.5 ng/ml
Image guided / organ localization based techniques are preferred.

31. Dose Constraints Definitive Therapy ( MSKCC; 81 Gy)

32. Adverse pathological / lab features :
Positive margins
Seminal vesicle invasion
ECE
Detectable PSA
pT3 disease
Gleason score 8 -10
Or as Salvage

33. Adjuvant
RT /
Salvage RT

34. Adjuvant
RT /
Salvage RT

35. Adjuvant
RT /
Salvage RT

36. Indicated in adverse path features ; detectable PSA with no evidence of
disseminated disease
Usually given within 1 year after RP and once operative side effects are
minimized
Salvage therapy is indicated in detectable PSA that increases on 2 subsequent
occasions . Most effective if pre treatment PSA is < 1 ng /ml
Recommended dosage : 64 to 68 Gy in std fractionation
Defined target volume is the prostate bed
Inclusion of pelvic nodes can be considered but not necessary.

37. Dose Constraints : OARs

38. RP + PLND
No fixation
If adverse features are + ------ RT / Observation
LN + ------- ADT / observation / ADT + Pelvic RT (Category 2B)

40. The T half of PSA is 3.1 days
PSA should be undetectable 4 weeks or more after RP
‘PSA doubling time’ expressed as the velocity in
nanograms/ml/year, or the PSA doubling time, in months or
years. The most important values to enter are the date/PSA value
for each PSA measured over the last 12 months. Alternately, if at
least three PSA values are available, enter all PSA values after
receiving radical prostatectomy, beginning with the lowest PSA
value.
The calculator is available at
http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx

41. Further RTOG –ASTRO phoenix consensus defined
Biochemical failure as
After EBRT with or without HT : PSA rise by 2 ng/ml or more above the nadir
PSA
The date of PSA is calculated at call and not back dated.