1) Post-operative radiotherapy (PORT) can reduce the risk of prostate cancer recurrence after radical prostatectomy for patients with adverse features like positive surgical margins or extracapsular extension. 2) Large randomized trials have shown that adjuvant radiotherapy (ART) within 6 months of surgery improves outcomes compared to observation or early salvage radiotherapy initiated at first signs of recurrence. 3) Salvage radiotherapy is an option for patients with rising PSA after surgery but no metastases, and can improve biochemical progression-free survival and cancer-specific survival when initiated promptly at low PSA levels.

1. Post Operative Radiotherapy(PORT)
in Prostate Cancer
By
Dr. N.SREEKANTH
DNB-RT

2. INTRODUCTION
• Prostate cancer is the most common
malignancy among men.
(In the United States, estimated new cases in
2017 are 161,380)
• No. 1 non-cutaneous cancer in men.
(Median age at diagnosis is 66)
• No. 2 cause of cancer death after lung cancer.

3. Staging

6. 2018 NCCN risk categories

8. Radical Prostatectomy

9. Indications of Radical Prostatectomy
Radical Prostatectomy is an appropriate therapy
for any patient with
• Clinically localized prostate cancer that can be
completely excised surgically
• Life expectancy of more than 10 years
• No serious comorbid conditions that would
contraindicate an elective operation

10. The procedure has evolved from
Laparoscopic Robot assisted approaches
Retropubic nerve sparing
Retropubic
Perineal

11. Transperineal Approach:
• Obese patients
– Disadvantages:
• Nerve sparing cannot be done
• Lymph nodes cannot be dissected
Retropubic approach:
Advantages:
• Lymphnode dissection can be done
• Nerve sparing surgery

13. Complications
• Blood loss Dorsal vein complex & Periprostatic
vessels
• Urinary incontinence: Urethral length &
Anastomotic strictures
(Bladder neck preservation may decrease the
risk of incontinence)
• Erectile dysfunction: Age at RP, Preoperative
erectile function, Degree of preservation of
the cavernous nerves.

16. Parsons et al.,
• Compared Retropubic Prostatectomy with
laproscopic and robotic assisted Prostatectomy.
• Decreased operative blood loss, decreased risk of
transfusion.
• Similar risk of Positive surgical margin.

17. Meta-analysis by Ficarra et al.,
• Urinary incontinence recovery better with
Robotic-Assisted Radical Prostatectomy
• Mainly influenced by: Patient
characteristics, Surgeon experience and
Surgical technique

18. After Radical Prostatectomy
No
Adverse
features
Adverse
features
with no
lymph
node
metastasis
Lymph
node
Metastasis
PSA
Persistence/
Recurrence

19. No Adverse features
• Monitoring
– PSA every 6-12 months for 5 year, then every year.
– DRE every year, but can be omitted if PSA
undetectable.

20. Adverse features with no lymph node metastasis
• EBRT (Adjuvant RT)
• OBSERVATION
Adverse pathologic features:
• Positive surgical margins
• pT3
• Extra-prostatic extension
• Seminal vesicle invasion

21. Lymph node Metastasis
• ADT+/- EBRT
• Observation

22. PSA Persistence/Recurrence
• Metastatic workup
– Negative: EBRT (Salvage RT)+/- ADT
– Positive: ADT+/- EBRT(Palliative RT)
Metastatic workup
• Endorectal MRI
• CT abdomen/pelvis
• Bone scan
• Prostate-specific antigen (PSA) history
& doubling time

23. • Biochemical progression was defined as a PSA
increase of 0.2 ng/mL or greater from nadir
(confirmed with a second increase), a continued
rise in PSA despite definitive treatment, or the
initiation of salvage ADT.
• Biochemical progression free survival (bPFS) was
defined as the time from completion of to
definitive treatment biochemical progression or
death, whichever came first.
• Time to distant metastases was defined as the
time from completion of definitive treatment to
the development of distant metastases.

24. Indications of postoperative radiation
therapy (PORT)
Adverse pathologic features:
• Positive surgical margins
• pT3
– Extra-prostatic extension
– Seminal vesicle invasion

25. Adjuvant Radiation After
Prostatectomy
• In the post-op setting, the prostate bed
• Negative margins : 64.8–66.6 Gy
• +Margins / Gross residual disease : 68.4– 72 Gy
• Three large randomized trials have
demonstrated that adjuvant radiotherapy to
60–64 Gy improves biochemical relapse-free
survival and potentially even overall survival in
some patients, compared to observation.

26. • 431 Patients with pT2-3 disease or positive surgical
margins.
SWOG 8794 (Thompson, J Urol 2009)

27. QOL study in 217 men (JCO 2008):
• Increased urinary and GI symptoms with RT,
though GI difference gone by 2 yrs.
• No difference in erectile function.
• QOL initially worse with RT, but improved with
time and favoured RT arm in long term.

28. SWOG 8794 Update(2009)
• Metastatic-free survival was significantly less
with radiotherapy
– HR 0.71 (95% CI 0.54-0.94; p=0.016)
– NNT- 12.2 men with pT3 to prevent 1 case of met
disease
• Overall Survival was improved significantly with
adjuvant radiation
– HR 0.72 (95% CI 0.55-0.96; p=0.023)
– NNT- 9.1 men with pT3 to prevent 1 death

29. • Adjuvant radiotherapy within 18 weeks after
radical prostatectomy with pT3N0M0 prostate
cancer
– Significantly reduces risk of PSA recurrence
– Significantly reduces risk of metastasis
– Reduced need for hormonal therapy
– Significantly increases survival
• SWOG 8794 trial demonstrated no Overall
survival benefit for the subset of patients with
confirmed undetectable PSA post operatively.

30. EORTC 22911 (Bolla, Lancet 2012;
Vander Kwast, JCO 2007)
• 1,005 men, pT3N0 with ECE or SVI,
+margin.
• No Grade 4 toxicity

31. • Improvements
– Biochemical progression-free survival
(Reduced need for salvage therapy)
– Local control
• Not in
– Clinical progression-free survival
– Overall survival
• Subgroup analysis: clinical progression-free survival
benefit
– Men aged <70 years
– Positive surgical margins

32. ARO 96-02 (Wiegel, Eur Urol 2014)
• 388 men, pT3N0, Margin positive or negative.
• Observation vs. Adjuvant RT 60 Gy
• 10-yr bPFS: 35 → 56%
• No difference in 10-yr OS or DM
Underpowered to assess OS and DMFS
• In RT arm
• Gr 2 GU toxicity- 2%
• Gr 2 GI toxicity - 1%
• Late Gr 3 toxicity - 0.3%

33. • Improved PFS after ART vs Observation
• Men with undetectable PSA do benefit from
ART post RP
• Subanalysis
– Men with +Margins are the most likely to benefit
from ART

34. • Approximately 30–35% of patients in the
SWOG and EORTC studies had a postoperative
PSA level >0.2 ng ml−1.
• There was no PSA progression in 30-40% of
these patients followed for 10+ years after
radical prostatectomy without any further
treatment, despite adverse pathologic
features.

36. Kang et al. found that, among men with capsular
perforation, PSMs, or seminal vesicle invasion
after surgery, only 17 percent actually went on
to have a true biochemical recurrence.

37. SALVAGE RADIOTHERAPY
• Salvage RT (SRT) is for the patient with a PSA
recurrence/persistance after surgery but no
evidence of distant metastatic disease.
• Biochemical (PSA) recurrence after surgery is
defined as detection of PSA concentration at
>0.2 ng/mL, with a second confirmatory level
detected at >0.2 ng/mL.

38. Pound et al, JAMA 1999; Freedland, JAMA 2005
• Men with rising PSA after RP at 10 yrs if
untreated
– 60% risk of developing DM and
– 20% risk of prostate cancer mortality
• Median time from PSA failure  DM is 8 yrs
• High GS or PSA doubling time <3 mo. only 3
yrs (worse prognosis)
• Median time from DM to death is <5 yrs

39. Predictive factors for LOCAL RELAPSE
• Slow rising PSA (b-Relapse>1 year after resection)
• PSA doubling time >12 months
• PSA Velocity(increase within 12 months <0.75 ng/ml)
• GS ≤7 at RP
• Surgical Margin +
• Negative LN
• Pisansky TM, J Urol;163: ,2000
• Stephenson A.J., et al JCO 25,(15): ,2007

40. Predictive factors for DISTANT RELAPSE
• Short PSA doubling time (<5 mhts)
• GS 8-10 at RP
• Seminal Vesicles +
• Positive LN
• pre RT PSA > 2 ng/ml
• Ward JF, Urol, 172:2244–2248,2004
• Stephenson AJ, Curr Treat Opt Onc 5: ,2004
• Pazona JF, J Urol 174:1282–1286,2005

41. Several nomograms are available to aid in
prognostication for patients who are
candidates for salvage therapy.

42. Tendulkar, JCO 2016
• 2,460 men with bF after RP
• Salvage RT (SRT) ± ADT
• Predictors of biochemical PFS: pre-SRT PSA,
GS, EPE, SVI, margins, ADT use, and RT dose.
• Predictors of DM: pre-SRT PSA, GS, SVI,
margins, and ADT

43. Stephenson Nomogram

44. UCSF-CAPRA (Cooperberg, J Urol 2005)
• 1,439 men s/p RP
• Followed in CaPSURE database
• Based on Cox analysis, points assigned by PSA,
GS, T stage, age, and % biopsy cores. CAPRA
score ranges 0–10.
• RFS at 5 yrs ranged from 85% for score of 0–1
to 8% for a score of 7–10.

45. CAPRA-S: A Tool for Predicting Outcomes
After Radical Prostatectomy

47. Genomic classifier (GC) (Den, JCO 2015)
22 gene-expression assay, Decipher® (GenomeDx Biosciences)
• 188 men with pT3 or + margins
• All treated with post-op RT
• 5-yr DM after RT: 0%, 9%, and 29% for low, average,
and high GC scores.
• Low GC score (<0.4), no differences in DM for adjuvant
vs. salvage RT.
• Higher GC scores (≥0.4), DM at 5 yrs was 6% for
adjuvant RT vs. 23% salvage RT.
• GC and pre-RP PSA were independent predictors of
DM.

48. PORTOS 24-gene score (Zhao, Lancet
Oncol 2016)
• 196 men s/p RP
• All treated with post-op RT
• Among men with high score, RT reduced 10-yr
DM 4% vs. 35% (validation cohort)

49. • Memorial Sloan Kettering has developed a
multi-institutional nomogram for salvage
radiotherapy after prostatectomy.

50. ROLE OF ADT WITH SALVAGE OR
ADJUVANT RADIOTHERAPY

51. RTOG 9601 (Shipley et al,. NEJM 2017)
• 760 men
• pT3pN0 or pT2pN0 with +margins who had bF
(PSA 0.2–4 ng/ml)
• Randomized to RT ± Bicalutamide (24 mo, 150
mg daily).
– Bicalutamide improved 12-yr OS (76% vs. 71%)
– Prostate cancer mortality (6% vs. 13%)
– DM (15% vs. 23%)
– 10-yr bPFS (46% vs. 30%).

52. • Greatest DM benefit
• GS 8–10
• PSA 1.5–4
• +margin
• Greatest OS benefit
• GS 7
• PSA 0.7–4
• +margin
• Early salvage radiotherapy (post
prostatectomy PSA between 0.1-0.5 ng/ml) has
greater DM & OS benefit.
S/E Bicalutamide
• Gynecomastia 70%
• Grade 3 liver toxicity <1%

53. GETUG-AFU16 (Carrie, Lancet Oncol 2016)
• 743 men
• pT2–4a and rising PSA 0.2 to <2
• 66 Gy salvage RT ± 6 months Goserelin
• Goserelin improved 5-yr bPFS 80% vs. 62%.
• Five year results revealed the addition of the GnRH
agonist improved freedom from biochemical and
clinical progression, with limited additional toxicity.

54. Ramey et al., (ASTRO 2016)
• Multi-institutional review of 1,861 post-op GS ≥7
patients.
• For GS 8–10, the combination of WPRT + ADT
improved 5-yr bPFS
– Prostate bed without ADT- 34%
– WPRT without ADT- 44%
– Prostate bed with ADT- 45%
– WPRT with ADT- 64%
• WPRT improved bPFS for GS 7 (67% vs. 53%), but
ADT did not.

55. Johns Hopkins Retrospective Review
(Trock ,JAMA 2008)
• 635 men with PSA >0.2 ng/mL post-RP.
• Retrospective review comparing no further treatment,
salvage RT, and salvage RT with hormonal therapy (HT).
• SRT had 3-fold in PCSS vs no SRT (HR 0.32, 95% CI
0.19-0.54)
– Limited to men with PSADT < 6mths
– SRT < 2yrs after recurrence
(Independent for path stage, Gleason score, surgical margin status)
• No added benefit with hormones
• SRT initiated > 2 yrs after recurrence provide no
significant increase in PCSS

56. • Salvage RT most effective for patients with:
– Low PSA at time of salvage (≪1 ng/mL)
– PSA velocity < 2 ng/mL in year before diagnosis
– Time to PSA failure >3 yrs after RP
– Pathologic GS ≤7, +margin(s), no LN involvement,
and no SVI
• Salvage RT can improve bPFS and CSS.

57. Comparison Between Adjuvant and Early-
Salvage Post-prostatectomy Radiotherapy for
Prostate Cancer With Adverse Pathological
Features
– William L. Hwang, MD, PhD1; Rahul D. Tendulkar,
MD2; Andrzej Niemierko, PhD1; et al
• JAMA Oncol. 2018;4(5):e175230.
doi:10.1001/jamaoncol.2017.5230

58. • Results Of 1566 patients,
– 1195 with prostate-specific antigen levels of
0.1 to 0.5 ng/mL received ESRT
– 371 patients with prostate-specific antigen
levels lower than 0.1 ng/mL received ART.
• Adjuvant RT compared with ESRT
– Higher freedom from biochemical failure: 69% vs 43%
– Freedom from distant metastases: 95% vs 85,
– Overall survival: 91% vs 79%
Patients with prostate cancer who have adverse
pathological features may benefit from post-
prostatectomy ART rather than surveillance
followed by ESRT.

59. Awaited future studies
• RADICALS
– Radiation and Androgen Deprivation In Combination After Local
Surgery
– Compare SRT vs ART, both with & w/o HT (6mth vs 24 mth)
– Primary outcome -Disease specific survival
• RAVES
– Radiotherapy Adjuvant Verus Early Salvage (non-inferiority trial)
– pT3 or +Margins and undetectable PSA
– Primary outcome -Biochemical recurrence
• Role of hormones + SRT
– RTOG 0534
• 3D-CRT / IMRT 64.8-70.2 Gy +/- 45 Gy to LN’s +/- 4-6 mths ADT

60. Radiotherapy Dose & Volumes
• Adjuvant RT:
– Negative margins : 64.8–66.6 Gyi n 1.8 to 2.0 Gy/fx
– +Margins / Gross residual disease : 68.4– 72 Gy
• Salvage RT (No clinical disease in fossa by exam or
MRI):
– 70 Gy in 1.8 to 2.0 Gy/fx
• Salvage RT (Clinical disease in fossa on imaging or
exam):
– 72 to 74 Gy in 1.8 to 2.0 Gy/fx.
(Entire prostate fossa may be treated to 70 Gy with a boost to the
clinical disease to 72 to 74 Gy.)

62. Consensus contours for patients with apical positive margins and biochemical recurrence

63. Consensus contours for patient with extracapsular extension at base and
involvement of seminal vesicle.

64. Short Term Side Effects
• Irritation of bladder, urethra and rectum
1. Urinary frequency
2. Slight burning or stinging with urination
3. Diarrhea or more frequent, softer bowel
movements, rectal soreness
4. Mild skin irritation is now rarely seen
5. Fatigue is common

65. Long Term Side Effects
• Chronic radiation cystitis or proctitis: 6% of the
men will have occasional episodes of blood in the
urine or with bowel movements, this usually
responds to medication (e.g. cortisone
suppositories)
– The risk of serious damage to the bladder and rectum
is now less than 1%
• Impotence: 30% of men with intact prostate have
problems after radiation, in men with previous
prostatectomy this is even higher.

66. SUMMARY
Adjuvant RT
• Patients who benefit the most
– Positive surgical margins
– Lower PSA levels.
• EORTC 22911 and ARO 96-02
– Significant improvement in biochemical recurrence
• SWOG 8794
– Improvement in metastasis free and overall survival

67. Salvage RT
• Treatment is more effective
– pre-treatment PSA is low and PSADT is long
• PSA should be monitored after radical
prostatectomy to trigger early salvage
radiotherapy
• Nomograms, and tumor based molecular assays:
Prognosticate risk of metastasis and prostate cancer-
specific mortality in men with adverse risk features
• Consider adding ADT, particularly for men with
high-risk features (RTOG 9601 used 2-yrs
bicalutamide; GETUG-AFU16 used 6-mo LHRH
agonist)

68. • Comparing adjuvant and early salvage radiotherapy show
an improvement with adjuvant for biochemical disease-
free survival, but little difference in overall survival.
• The advantage of waiting is that it may allow for better
recovery of continence and erectile function after
surgery in at least some patients.
• Most literature reports on older RT techniques. Unclear
whether newer techniques result in fewer differences
b/w ART and SRT outcomes
Men with adverse pathology or postoperative PSA
kinetics should be discussed in Multi disciplinary
tumor board regarding immediate or delayed
postoperative radiotherapy

70. THANK YOU