LOCALLY ADVANCED PROSTATE CANCER

1. Treatment of Locally Advance CA Prostate and
Practical Approach for Raising PSA value after
definitive Local therapy
Dr Abdul Rehman
Post Graduate Resident
Urology Unit II,
Mayo Hospital Lahore

2. Definition
Clinically detectable locally advanced CA
Prostate include
Cancer extension beyond the prostate capsule into
• Periprostatic tissue (T3a )
• Involvement of seminal vesical (T3b )

3. For Patients treated with radical prostatectomy
• Histological evidence of extraprostatic extension and
surgical margin status are used to define locally advanced
disease.
According to EAU Risk Group for BCR, Locally advance Ca
prostate is in High Risk group (any PSA, any GS, any ISUP
grade plus T3, T4, No, or N1)

4. Treatment of locally advanced PCA
A local treatment combined with a systemic
treatment provides the best outcome, provided
the patient is ready and fit enough to receive
both
Treatment of T3 T4 No
1) RAICAL PROSTATECTOMY
• Radical prostatectomy is offered to patients with T3 –T4
disease as a part of multimodal therapy.

5. • While concurrent extended bilateral extended lymph
node dissection in high risk CA Prostate provides
additional staging and possible therapeutic value.
• There are survival data suggesting that RP should not
be abandoned if lymph node metastases are identified
at the time surgery (frozen section of node should not
be done).
• The removal of prostate may reduce the risk of
development of local progression and metastasis.
(Cyto-reductive surgery)

6. • RP demonstrated over 60% CSS at 15 years and over
75% OS at 10 years against EBRT and ADT

7. 2) EXTERNAL BEAM RADIATION THERAPY
• Offer patients with locally-advanced disease intensity-
modulated radiation therapy (IMRT)/ volumetric
modulated arc therapy (VMAT) plus image-guide
radiation therapy in combination with long-term
androgen deprivation therapy (ADT).
• Offer long-term ADT for at least 2 years.

8. • The 5 years overall survival was 79% compared to 62%
in group treated with EBRT alone.
• The 5 years CSS was 85% compared to 48% in group
treated with EBRT alone.

9. Therapeutic option outside surgery and
radiotherapy
Investigational Therapies
Cryotherapy, HIFU or focal therapies have no role

10. 3) Androgen Deprivation Therapy Monotherapy
Only offer ADT monotherapy to those patients
unwilling or unable to receive any form of local
treatment if
• They have a prostate specific antigen doubling time <12
months.
• Prostate specific antigen >50ng/dl.

11. • A poorly differentiated tumors
• Troublesome local disease symptoms
Non steroidal anti androgen such as Bicalutamide
150mg has equivalent efficacy to ADT with reduce side
effects.

12. Treatment for T3-4 , N1 disease
• Lymph node metastasised PCa is where options for
local therapy and systemic therapies overlap.
• Approximately 5% to 10% of newly diagnosed PCa
patients have synchronous suspected pelvic nodal
metastases on conventional imaging (CT/bone scan)
without bone or visceral metastases (cN1 M0 stage).

13. •Meta-analyses have shown that PSMA-PET/CT prior
to primary treatment in advanced PCa detected
disease outside the prostate in 32% of cases despite
prior negative conventional imaging using bone scan
and pelvic CT/MRI
•A RCT assessing PSMA-PET/CT as staging tool in high-
risk PCa confirmed these findings and showed a 32%
increase in accuracy compared with conventional
imaging for the detection of pelvic nodal metastases

14. • The management of cN1M0 PCa is mainly
based on long-term ADT combined with a local
treatment.
• There is advantage in both OS and CSS after
local treatment (RT or RP) combined with ADT
as compared to ADT alone.

15. • The addition of a brachytherapy boost to ADT plus
EBRT was not associated with improved OS
• systemic treatment with abiraterone acetate,
docetaxel or zoledronic acid did not provide any OS
benefit when stratifying by M0 and N+ status.

16. Guidelines for Radial treatment of locally
advance disease

17. Adjuvant treatment after radical
prostatectomy
Introduction
• Adjuvant treatment is by definition additional to the primary or
initial therapy with the aim of decreasing the risk of relapse.
• A post-operative detectable PSA is an indication of persistent
prostate cells

18. Risk of relapse
• ISUP grade > 2 in combination with T3a particularly T3b
• positive surgical margins
• These are high risk of progression, which can be as high as 50% after 5 years
• Irrespective of the T stage, the number of removed nodes, tumour volume within
the LNs and capsular perforation of the nodal metastases are predictors of early
recurrence after RP for pN1 disease
• A LN density (defined as ‘the percentage of positive LNs in relation to the total
number of analyzed/removed LNs’) of over 20% was found to be associated with
poor prognosis.
• The number of involved nodes seems to be a major factor for predicting relapse
• The threshold considered is less than 3 positive nodes from an ePLND

19. Biomarker based risk stratification after RP
• The Decipher gene signature consists of a 22-gene panel representing
multiple biological pathway
• Was developed to predict systemic progression after definitive
treatment.
• A meta-analysis of five studies analysed the performance of the
Decipher Genomic Classifier (GC) test on men post-RP. Decipher GC
remained a statistically significant predictor of metastasis
• A systematic review of the evidence for the Decipher GC has
confirmed the clinical utility of this test in post-RP decision-making

20. Immediate (adjuvant) post-operative external
irradiation after RP (cN0 or pN0)
• Immediate post-operative RT (adjuvant RT), demonstrating an
advantage in high-risk patients (e.g., pT2/pT3 with positive surgical
margins and GS 8–10) Post-RP
• It must be emphasized that PSA was undetectable (< 0.1 ng/mL)
• detectable PSA (0.1 and 0.5 ng/mL) would now be considered for
salvage therapy rather than ART
• It is important to note that the indication for ART changed over the
last ten years with the introduction of ultra-sensitive PSA-tests,
favouring early SRT

21. Adjuvant androgen ablation in men for No
disease
• Adjuvant docetaxel after RP for locally-advanced PCa showed that
adjuvant docetaxel did not confer any oncological benefit
• Adjuvant androgen ablation with bicalutamide 150 mg daily for
locally-advanced disease after RT showed a possible benefit for PFS
but not OS

22. Adjuvant treatment in pN1 disease
Adjuvant androgen ablation alone
• The combination of RP and early adjuvant HT in pN+ PCa has been
shown to achieve a 10-year CSS rate of 80% and has been shown to
significantly improve CSS and OS in prospective RCTs

23. Adjuvant radiotherapy combined with ADT
• Maximal local control with RT to the prostatic fossa appeared to be
beneficial in PCa patients with pN1 after RP, when treated ‘adjuvantly‘
with continuous ADT
• The beneficial impact of adjuvant RT on survival in patients with pN1
PCa was highly influenced by tumour characteristics
• Men with low-volume nodal disease (< 3 LNs), ISUP grade 2–5 and
pT3–4 more likely to benefit from RT after surgery

24. • US National Cancer Database study including 8,074 pN1 patients
reports improved OS after ADT plus EBRT
• Radiotherapy should be given to the pelvic lymphatics and the
prostatic fossa
• In a systematic review, RT with or without ADT was associated with
improved survival in men with locally-advanced disease

25. Observation of pN1 patient after RP and
extended LN Dissection
• patients with limited nodal disease (1–2 positive LNs) showed
favourable oncological outcomes and did not require additional
treatment.

26. Guidelines for adjuvant treatment in pN0 and
pN1 disease after radical prostatectomy

27. Palliative treatment of locally advance CA
Prostate
• ADT may relief tumor compression of distal ureter in
previously untreated patients.
• Palliative EBRT may be useful for treatment of persistent
prostatic hematuria or perineal pain.

28. Guidelines for non-curative or palliative
treatments in prostate cancer

29. Persistent PSA after radical prostatectomy
• Between 5 and 20% of men continue to have detectable or persistent
PSA after RP
• When defined in the majority of studies as detectable post-RP PSA of
> 0.1 ng/mL within 4 to 8 weeks of surgery
• It may result from persistent local disease, pre-existing metastases or
residual benign prostate tissue

30. Natural history of persistently elevated PSA
after RP
• Several studies have shown that persistent PSA after RP is associated
with poor prognosis because it is the feature of more advanced
disease (such as positive surgical margins, pathologic stage > T3a,
positive nodal status and/or pathologic ISUP grade > 3)
• Predictors of PSA persistence were higher BMI, higher pre-operative
PSA and ISUP grade > 3
• In patients with PSA persistence, one and 5-year BCR-free survival
were 68% and 36%, compared to 95% and 72%, respectively, in men
without PSA persistence

31. • In a multivariable analysis the presence of a persistently detectable PSA
post-RP was associated with a 4-fold increase in the risk of developing
metastasis.
• In another multivariable analysis the PSA slope after RP (as calculated using
PSA levels 3 to 12 months after surgery) and pathological ISUP grade were
significantly associated with the development of distant metastases.
• improvements in the sensitivity of PSA assays now allow for the detection
of PSA at much lower levels.
• Moreira et al., demonstrated that failure to achieve a PSA of less than 0.03
ng/mL within 6 months of surgery was associated with an increased risk of
BCR and overall mortality

32. Imaging in patients with persistently elevated
PSA after RP
• Standard imaging with bone scan and MRI has a low pick-up rate in
men with a PSA below 2 ng/mL
• PSMA PET/CT has been shown to identify residual cancer with
positivity rates of 33%, 46%, 57%, 82%, and 97%, in men with post-RP
PSA ranges of 0–0.19, 0.2–0.49, 0.5–0.99, 1–1.99, and > 2 ng/mL,
respectively which can guide SRT planning
• It is found that in the presence of persistent PSA the majority of
patients already had metastatic pelvic LNs or distant metastases
which would support a role of PSMA PET/CT imaging in guiding
(salvage) treatment strategies

33. Impact of post-operative RT and/or ADT in
patients with persistent PSA
• benefit of SRT in patients with persistent PSA remains unclear due to
a lack of RCTs, however, it would appear that men with a persistent
PSA do less well than men with BCR undergoing RT
• In multivariable models, SRT was associated with lower risk for death
and lower cancer-specific death.
• These survival outcomes in patients with persistent PSA who
underwent SRT suggest its benefit

34. • But Persistent PSA outcomes are worse than for men experiencing BCR
• It is clear from a number of studies that poor outcomes are driven by the
level of pre-RT PSA, the presence of ISUP grade > 4 in the RP histology and
pT3b disease
• Addition of ADT may improve PFS
• In a prospective RCT, 74 patients with PSA persistence (20%) received
immediate SRT only (66 Gy per protocol ). The 10-year clinical relapse-free
survival was 63%
• In another trial comparing RT with RT plus short-term ADT for post-RP PSA
persistence (0.2–2.0 ng/mL) reported good tolerability of the combined
treatment

35. Conclusion
• The available data suggest that patients with PSA persistence after RP
may benefit from early aggressive multimodality treatment, however,
the lack of prospective RCTs makes firm recommendations difficult.

36. Recommendations for the management of
persistent PSA after radical prostatectomy

37. Thanks