Locally advanced Prostate Cancer

1. LOCALLYLOCALLY
ADVANCEDADVANCED
PROSTATE CANCERPROSTATE CANCER
Gaurav Nahar
DNB Urology Resident
MMHRC, Madurai

2. Ca P STAGING

3. DEFINITION
Locally Advanced Prostate Cancer(LAPC):
• Tumors with spread outside of the prostate
capsule (clinical stage T3a), or
• involvement of seminal vesicles (cT3b), or
• involvement of adjacent organs (cT4), or
• regional or lymph node involvement without
distant metastasis (T3-4 N± M0), or
• any combination of these.

4. D'AMICO RISK
CLASSIFICATION

5. • Despite the stage migration a/w PSA
testing and growing number of low-stage
and organ-confined tumors, at least 10%
of newly diagnosed CaP cases have
LAPC (T3NX/+M0).
• Currently, no consensus exists regarding
the optimal management of LAPC.

6. • Treatment of LAPC by any single modality
is a/w significant risk of recurrent disease.
• Two analyses suggest that men with
higher-risk disease characteristics may
have reductions in cancer-specific
mortality and metastatic progression after
radical prostatectomy(RP) compared
with other treatment modalities.

7. RISK ASSESSMENT
• Ability to assess pathologic stage permits
better pretreatment counseling of patients,
more appropriate selection of therapy and
consideration of those with more advanced
disease for novel clinical trials.
• Most important pathologic criteria predicting
prognosis after RP are Gleason score, surgical
margin status, and presence of non–organ-
confined disease (e.g.extracapsular extension,
seminal vesicle invasion, lymph node
involvement).

8. • Serum PSA, Gleason score, and T stage
are more useful together than alone in
predicting final pathological stage.

9. IMAGING IN LAPC
• TRUS(Traditional gray scale): limited ability to
improve cancer staging.
• Largely operator-dependent and cannot
differentiate between T2 & T3 tumours with
sufficient accuracy to be recommended for
routine staging.
• Directed biopsy of seminal vesicles or prostate
capsule can be obtained to confirm cT3 disease.
• Candidates for SV biopsy: T stage > 2a and
serum PSA > 10 ng/mL, & Positive biopsies from
the base of the prostate.

10. • Addition of Color &
Power doppler to
TRUS to improve
sensitivity- still under
investigation.

11. • Endorectal MRI uses a magnetic coil placed in the
rectum to achieve better visualization of zonal
anatomy of the prostate and may delineate subtle
distinctions b/w T2a/b &T3 disease.
• Role of MRI with or without MR Spectroscopy for
tumor staging- controversial.
• >3 cores involved with cancer, abnormal findings on
DRE, and PSA >10 ng/mL undergoing radical
prostatectomy, specificity of MRI in predicting pT3
disease ~ 95%.
• Thus use of MRI may be best limited to those
patients with higher-risk features.

12. NODAL STAGING
• Abdominal CT and mpMRI indirectly assess nodal
invasion by measuring lymph node diameter.
• Drawbacks: Low sensitivity and microscopic invasion
cannot be detected.
• Using a 10-mm threshold, CT or mpMRI sensitivity is <
40%.
• Currently available most optimal method for N-staging is
open or laparoscopic lymphadenectomy: Image guided
intraoperative Sentinel Node detection (experimental).

13. NOVEL MARKERS
• Traditional clinical and pathologic
parameters are limited in their ability to
accurately predict local tumor extent
before treatment.
• Chromosomal rearrangements involving
the androgen-regulated gene TMPRSS2
and the ETS family genes are associated
with higher pathologic stage.

15. TRENDS IN INCIDENCE
& Rx
• Fewer men are presenting with locally
advanced prostate cancer.
• There is an increase in organ-confined
cancers identified after RP.
• There is an increasing use of treatment
modalities other than surgery for high-risk
prostate cancers.

16. • High risk of recurrence in clinically advanced
disease, both cT3a and cT3b-T4.
• Bone scans are indicated in these + PSA > 20
ng/mL or Gleason score 8 or higher;
• Pelvic CT/MRI is also indicated for cT3-T4
disease or if calculated probability of lymph node
involvement >10%.

17. • In general, RP + extended PLND is
reserved for high-risk men with low-
volume tumors that can be completely
excised.
• Alternative treatment strategy for these
locally advanced disease and higher risk
of biochemical failure is AD + RT.

18. LAPC:
MANAGEMENT
OPTIONS

19. DEFERRED TREATMENT

20. RADICAL
PROSTATECTOMY
Use of RP for m/m of LAPC has decreased d/t:
• Recognition that RP alone is insufficient.
• Improved risk assessment & pt.stratification
• Advances in RT delivery, and
• Recognition that combined modality treatment
(e.g., RT + AD) improved outcomes compared
with monotherapy.
Nevertheless, RP can cure some high-risk
cases, and addition of adjuvant and combined
therapy may further improve outcomes of
surgery alone.

21. • In recent years, there is a renewed interest in
surgery for LAPC.
• Provided that tumour is not fixed to pelvic
wall, or there is no invasion of urethral
sphincter, RP is a reasonable first step in
selected low-volume LAPC cases.
• Extended pLND should be performed in all
high-risk CaP cases, as estimated risk for
positive lymph nodes is 15-40%

22. • RP alone can result in cancer-free survival
in at least half of men at 8 to 10 years
despite clinically advanced disease.
• Risk of cancer recurrence after surgery
can be quantitated on the basis of
1.pathologic stage,
2.cancer grade, and
3.surgical margin status.

23. Rationale for RP in patients with cN0 but
pathologically confirmed lymph node
invasion (pN1) CaP:
• Studies favour completed RP vs. abandoned RP
in patients found to be N+ at the time of surgery.
• RP results in superior survival of patients with
pN+ CaP after controlling for lymph node tumour
burden and frozen sections of lymph nodes
intraoperatively are no longer recommended.

24. • Extended LND includes removal of nodes
overlying external iliac artery & vein,
nodes within obturator fossa located
cranially and caudally to obturator nerve,
and nodes medial and lateral to internal
iliac artery.
• Adding common iliac area and presacral
area further increases clearance.

25. Neoadjuvant Androgen Deprivation(NAD):
• NAD therapy before RP in LAPC does not
improve cancer-specific or overall survival.

26. Adjuvant androgen ablation in men with
pN1 disease:
• Combined RP + early adjuvant HT in pN+
CaP achieves a 10-year CSS rate of 80%.
• pN+ after RP, early adjuvant HT
significantly improve CSS and OS in a
prospective randomised trial.

27. • Benefits vs. side effects of long-term HT.
• Follow-up of PSA and delaying initiation of
HT until PSA level rises is an acceptable
option in selected cases with < 2
microscopically involved lymph nodes in
an extended nodal dissection.

28. Neoadjuvant Chemotherapy and
Chemotherapy–Hormonal Therapy:
• On the basis of success of taxanes in
hormone refractory prostate cancer,
interest has increased in earlier use of
chemotherapy in high-risk patients or
LAPC.

29. • 3-month combination regimen = two 6-week
cycles of ketoconazole and doxorubicin
alternating with vinblastine and estramustine.
• In addition, concurrent AD with an LHRH agonist
and antiandrogen.
• 4 to 6 months of NAD with paclitaxel,
estramustine, and carboplatin androgen-
dependent, high-risk prostate cancer.
• Single-agent docetaxel.

30. Adjuvant Radiation Therapy:
• Withholding regional or systemic therapy until
after prostate is removed may
1. prevent delay in time to surgery,
2. reduce operative morbidity, and most
importantly
3. identify those men with adverse pathologic
features or evidence of residual disease who
truly need additional therapy, thereby avoiding
overtreatment in those with more favorable
disease.

31. • Adjuvant radiation therapy improves local
control and reduces biochemical relapse
in selected patients after RP and likely
improves metastasis-free and overall
survival.
• Benefit of adjuvant radiation therapy may
be greatest in cases of positive surgical
margins.
• Improved outcomes of adjuvant radiation
therapy are associated with dose
escalation (64 Gy).

32. • Men with seminal vesicle invasion who
achieve a low PSA level (<0.3 ng/mL) after
RP or have positive surgical margins:
more favorable group for adjuvant RT.
• Conversely, more advanced disease
never reaching an undetectable PSA
level- a poor prognostic group likely
harboring unrecognized lymph node or
distant disease.

33. • RT of the prostatic fossa is beneficial in
CaP patients with pN1 after RP, treated
adjuvantly with continuous ADT.
• Optimal field (prostatic fossa only or whole
pelvis) remains unclear.

34. Adjuvant chemotherapy:
• Adjuvant chemotherapy after RP in LAPC
should only be considered in a clinical
trial.

35. RADIATION THERAPY
• In higher-risk patients, improved
biochemical control observed with 81 Gy
or more for EBRT.
• Greatest benefits in the high-risk group
with PSA > 10 ng/mL.
• Intensity-modulated radiotherapy (IMRT),
with or without image-guided radiotherapy
(IGRT), is the gold standard for EBRT.

36. • In high-risk tumors or LAPC, monotherapy
with RT or permanent interstitial
brachytherapy is inadequate.
• Outcomes improved by combining RT
with AD, often in conjunction with whole-
pelvis irradiation.

37. Neoadjuvant Androgen Deprivation and
Radiation Therapy:
• Theoretical benefits of AD(LHRH) before
RT in LAPC are: ability to reduce target
volume, & potential cytotoxic synergy of
radiation and hormone manipulation.
• Observations support Neoadjuvant &
concurrent AD with RT, also a benefit of
prolonged AD.

38. • ADT starts either at the onset of RT (for
adjuvant ADT) or 2 or 3 months before (for
neoadjuvant), but concomitant component
is crucial to potentiate RT.
• Long-term ADT, ranging from 2 to 3 years
is recommended for LAPC rather than
short term (6-months).

39. Adjuvant Androgen Deprivation and Radiation
Therapy:
• Adjuvant AD after radiation therapy may benefit
those with very high-risk disease.
• Duration of such adjuvant AD is uncertain (2
months neoadjuvant+2 months concurrent +/- 24
additional months).
• A limited period of AD (2 to 4 months) is
appropriate for intermediate-risk cancers; more
prolonged AD may be beneficial for high-risk
disease characteristics, including high-stage
cancers, or high pretreatment serum PSA
values.

40. Radiation Therapy and Chemotherapy:
• Less well-studied in LAPC.
• Concerns about additive toxicities.
• Estramustine and vinblastine concurrently
with RT (total, 65 to 70 Gy) in locally
advanced disease.
• Estramustine-based regimen also
examined with etoposide before and
during definitive RT.

41. FOCAL ABLATIVE
THERAPY
• Cryoablation & High-Intensity Focussed
Ultrasound(HIFU).
• Ability to treat local disease within the
prostate by these modalities may play a
role even in LAPC, most likely in
combination with AD or other systemic
therapy.

42. INTERMITTENT AD
• To minimizing AD-related morbidity.
• Rx protocol: total AD until PSA level < 4.0 ng/mL
between 24 and 32 weeks, after which treatment
withheld after 36 weeks. PSA level then
monitored and treatment recommended when
PSA level reaches either pretreatment level
(when <15 ng/mL) or 15 ng/mL (when the initial
PSA level was higher than that).

43. QUALITY OF LIFE
• Multimodal approach with AD + RT
increases relative toxicity compared with
each intervention alone.
• Benefits of adjuvant AD + RT for LAPC,
both short and long term outweighs the
associated side effects.
• Even considering the increased incidence
of side effects of long-term AD, this
approach is better than short-term AD.

44. TREATMENT SUMMARY

48. ThankThank
YouYou !!!!