detail presentation on management of prostaste cancer

1. Management of prostate cancer

2. • Low risk:
PSA < 10ng/ml and Gleason < 6 and
The percentage of involved cores is < 50% or
Intermediate risk with only 1 positive core
• Intermediate risk:
Gleason score of 7 or PSA of 10-20
Low risk with > 50% of positive cores or
High risk and only 1 positive core
• High risk:
Gleason > 8 or PSA > 20 and more than 1 positive core
Or intermediate risk and more than 50% positive cores

3. • Watchful waiting refers to monitoring the
patient until he develops metastases that
require palliative treatment.
• Active surveillance or expectant management
allows delayed primary treatment if there is
biochemical or histologic evidence of cancer
progression
Dall’Era et al, 2012

4. Active surveillance(AS)
• Observed with semiannual PSA
determinations and DRE and annual biopsies
• Indicated
– Patients with low-risk cancer and a life expectancy
<10 years
– Patients with very low-risk cancer and a life
expectancy <20 years
• African american and BRCA 2 mutation
carriers are not suitable for AS

5. • Carter et al.
– Cohort of 769 men with very-low-risk prostate
cancer and low PSA density
– 41% of patients had been treated at 5 years, and
59% at 10 years
– Median time to treatment was 6.5 years.
– Cancer control after delayed therapy was excellent
• AS is now widely recommended for most men with
low-risk cancer, based on the lack of survival benefit
of immediate surgery versus observation at 12 years
in the PIVOT trial

6. • Intervention is recommended
– Gleason pattern 4 5 or is present,
– More than two biopsy cores are involved, or
– More than 50% of a biopsy core is involved.
– Progression is more likely in patients who have cancer
present on every biopsy procedure.
– The absence of cancer on repeated biopsy significantly
decreases the likelihood of progression (Carter et al,
2007).
– Biopsy criteria have been reported to be more
accurate than PSA criteria in predicting progression

7. • Overdiagnosis often refers to a cancer detected
by screening that would not be detected during
the patient’s lifetime without screening or would
never cause disability or death
• 50% or more of prostate cancer cases are
overdiagnosed (Etzioni et al, 2002; Draisma et al,
2003)
• At present, no tumor marker or algorithm can
identify indolent tumors with certainty

8. • Disadvantages
– Up to one half of patients are upgraded on the basis
of the radical prostatectomy specimen
– Repeated biopsies are always subject to sampling
errors (Harnden et al, 2008) and
– May induce fibrosis in and around the prostate gland
that could compromise subsequent nerve-sparing
surgery, rendering it impossible to perform in more
than half of patients (Barzell and Melamed, 2007)
– Trigger inflammation leading to PSA fluctuations that
are difficult to interpret
– Patients undergoing active surveillance and radical
prostatectomy have a similar quality of life in most
domains at 5 years of follow-up
– 6 to 8 years, active surveillance groups have more
anxiety and depression

9. Radical Prostatectomy
• Gold standard
• Hormone therapy and chemotherapy are never
curative
• Not all cancer cells can be eradicated consistently
by radiation or other physical forms of energy,
even if the tumor is contained within the prostate
capsule
• If the prostate gland remains in situ, it is possible
for new prostate cancers to develop in the
retained prostatic epithelium

10. • Advantage of radical prostatectomy
– Possibility of cure with minimal collateral damage to
surrounding tissues if it is skillfully performed
– Provides more accurate tumor staging by pathologic
examination of the surgical specimen.
– Treatment failure is more readily identified,
– Tumor recurrence after radical prostatectomy can be
successfully treated with potentially curative postoperative
radiotherapy
– Postoperative course is much smoother than in the past.
• Few patients require nonautologous blood transfusions.
• The hospital stay is usually 1 to 3 days, and operative
mortality is rare in the modern era
– Radical prostatectomy significantly reduces local tumor
progression and distant metastases and improves
cancerspecific and overall survival rates compared with
watchful waiting

11. • Disadvantages of radical prostatectomy
– Necessary hospitalization and recovery period; a
– Possibility of incomplete tumor resection,
– If the operation is not performed properly or if the
tumor is not contained within the prostate gland
– Risk for erectile dysfunction and urinary incontinence.
• Erectile dysfunction and rectal complications are less likely
with nerve-sparing surgery than with radiotherapy, and
• Good treatment options are available to treat both urinary
incontinence and erectile dysfunction.
– Results reported from high-volume centers are more
favorable than those from national surveys

12. • Surgical Approaches to Radical Prostatectomy
– Open
• Perineal
• Retropubic
– Minimal invasive
• Laparoscopic
–Transe peritoneal
–Retroperitoneal
• Robotic

13. • The principal objective of radical prostatectomy is to
completely excise the cancer
• Other objectives are remain continent and preserve potency
• The key to preserving urinary continence is to perform a
meticulous dissection, avoiding injury to the external urinary
sphincter.
• Meticulous dissection is also required to preserve the
neurovascular bundles
• Hemostatic sutures or clips may be used to control bleeding
from the neurovascular bundles. Use of electrocautery or a
harmonic scalpel risks irreversible thermal injury to the
neurovascular bundles
• The prostatic pedicles are suture ligated or hemoclipped and
divided close to the gland, avoiding incision into the prostatic
capsule.
• In performing the seminal vesicle dissection, care must be
taken to avoid injury to the neurovascular bundles situated
immediately lateral and posterior to thems

14. • Perineal
– Less blood loss
– Short operative time
– Disadvantages
• Does not provide access to lymph nodes
• High rates of rectal injury
• Occasional post operative fecal incontinence
• Difficulty to spare cavernous nerves

15. • Retropubic
– Familiarity with surgical anatomy
– Low risk of rectal injury and fecal incontinence
– Wide exposure
– Ready access to pelvic lymph nodes
– Low risk of cancer at surgical margin
– Preservation of neurovascular bundle

16. • Laparoscopic RP
– Associated with less bleeding, better visualization, less
postoperative pain, and shorter convalescence than the
standard open approach
– Hemostasis in the neurovascular bundles is difficult to
achieve without applying
– Thermal injury to the neurovascular bundles
• Relative difficulty in rapidly placing hemostatic sutures or applying
hemostatic clips laparoscopically.
• Heat from a harmonic scalpel or electrocautery can irreversibly
damage the cavernous nerves
– Rectal, ureteral, and vascular injuries and anastomotic
leaks have also been more common with laparoscopic
prostatectomy in some studies

17. • The early reported rates of positive surgical
margins have been higher with laparoscopic
prostatectomy, and the adequacy of cancer
control is as yet uncertain because of lack of
long-term results
Touijer et al, 2009

18. • Robotic RP
– Greater technical ease for the surgeon, especially for tying
sutures and performing the vesicourethral anastomosis
– Lower blood loss three-dimensional (3D) visualization
– Enhanced dexterity
– No superiority was seen between robotic and open radical
prostatectomy for functional or oncologic outcomes
• Pierorazio et al, 2013a; Silberstein et al, 2013
– Robotic prostatectomy was associated with a trend toward
more urinary incontinence and no difference in sexual
function compared with open radical prostatectomy
• Barry et al, 201
– Significantly lower transfusion rate and shorter hospital
stays compared with open radical prostatectomy (Tewari et
al, 2012; Sammon et al, 2013) but a
– higher rate of incisional hernias (Carlsson et al, 2013).

20. • The importance of the surgeon’s experience in
reducing complications is well documented
(Vickers et al, 2007, 2009; Klein et al, 2008;
Abboudi et al, 2014; Thompson et al, 2014;
Vickers, 2014)
• Patients considering surgical treatment of
their prostate cancer should be not to choose
a technique but to choose an expert in a given
technique

21. • Patient selection
– Healthy and free of comorbidities
– Life expectancy of at least 10 years
– Generally accepted upper age limit for radical
prostatectomy is about 76 years
– Neoadjuvant hormone therapy does not enhance
the resectability of prostate cancer and often
increases the difficulty of performing nerve-sparing
surgery
– Neoadjuvant chemotherapy rarely produces
pathologic complete responses

22. – Nerve-sparing surgery is questionable
• Extensive cancer in the biopsy specimens
• Palpable extraprostatic tumor extension
• Serum PSA level above 10 ng/mL
• Biopsy Gleason score higher than 7
• Poor-quality erections preoperatively
• Current and future lack of a sexual relationship
• Medical conditions that may adversely affect erections
(e.g., diabetes mellitus, hypertension, psychiatric
diseases, neurologic diseases, or medications that
produce erectile dysfunction)

23. • Surgical Technique
1. Pelvic lymphadenectomy
2. Opening of the endopelvic fascia and limited incision of the
puboprostatic ligaments
3. Suture ligation and transection of Santorini dorsal venous
complex
4. Dissection of the urethra at the apex of the prostate and
transection of the urethra (sometimes the anastomotic
sutures are placed at this point in the operation)
5. Dissection of the prostate from the neurovascular bundles
6. Securing and transection of the prostatic pedicles
7. Transection and reconstruction of the bladder neck
8. Dissection of the seminal vesicles and ampullary portions of
the vasa deferentia
9. Performance of the vesicourethral anastomosis

24. • Failure after RP was defined as a rising serum
PSA >0.2 ng/ml, clinical evidence of local or
distant recurrence, or the initiation of
adjuvant radiotherapy or hormonal treatment
• At 5 years 84% of patients, at 10 years 78%,
and at 15 years 73% were free of progression

25. • The hazard of prostate cancer–specific
recurrence continues to increase for at least
15 years after radical prostatectomy, and the
risks for mortality may increase for 25 years or
more (Shikanov and Eggener, 2011; Bill-
Axelson et al, 2014)
• It is important to continue to monitor patients
long after surgery

26. • Pelvic Lymph Node Dissection
– Restrict PLND at the time of RP to men with a ≥2% risk of
positive nodes according to a contemporary nomogram
• Limited Versus Extended Pelvic Lymph Node Dissection
– No prospective studies have demonstrated the optimal
anatomic limits of a PLND for prostate cancer
– PLND that includes the external iliac, hypogastric, and
obturator node packets is feasible in both open and
minimally invasive RP, and carries no greater risk than a
PLND limited to the external iliac nodes alone
– The more extensive the PLND, the greater the number of
LN removed, and the greater the number of positive
nodes.

27. • Therapeutic Benefit of Pelvic Lymph Node
Dissection
– Potential therapeutic benefit of extended PLND,
particularly in men with only one or two positive
nodes and Gleason score ≤7 in cancer identified in the
RP specimen
– In a series of patients with positive LN treated at
Johns Hopkins Hospital, men who had an extended
PLND were less likely to develop BCR at 5 years,
compared with men who underwent a limited PLND

29. • Complications
– Early complications include hemorrhage; rectal,
vascular, ureteral, and nerve injury; urinary leak or
fistula; thromboembolic and cardiovascular
events; urinary tract infection; lymphocele; and
wound problems
– Late complications of radical prostatectomy are
erectile dysfunction, urinary incontinence,
inguinal hernia, incisional hernia with laparoscopic
and robotic prostatectomy, and urethral stricture

30. • Urinary Continence
– High-volume radical prostatectomy surgeons, more
than 90% of men recover complete urinary
continence.
– The return of urinary continence is associated with
the patient’s age:
• Approximately 95% of men younger than 60 years can attain
pad free urinary continence after surgery; 85% of men older
than 70 years regain continence.
– Relatively few require implantation of an artificial
urinary sphincter or a sling procedure for stress
urinary incontinence.

31. • Erectile Function
– The return of erectile function after radical
prostatectomy correlates with the age of the patient,
preoperative potency status, extent of nerve-sparing
surgery, and era of surgery
– Erections usually begin to return as partial erections 3
to 6 months after surgery and may continue to
improve for up to 3 years or more
– Patients should be encouraged to use erectile aids
postoperatively, including PDE5 inhibitors,
intraurethral suppositories, intracavernosal injections,
or vacuum erection devices

32. • Scandinavian randomized trial (SPCG-4)
– 695 unscreened men with clinically localized prostate
cancer
– Over 23 years of follow-up,
– RP compared with watchful waiting
• Reduced the risk of death from any cause by 29%
• Risk of death from prostate cancer by 44% (an absolute
difference of 11%).
• The need for subsequent ADT was reduced by 51%,
• Clinical local recurrence was reduced by 66%.

33. • Prostate Cancer Intervention Versus Observation Trial
(PIVOT)
– United States and randomly assigned 731 men with clinically
localized prostate cancer to RP or observation
– mean age was 67, the median PSA level was 7.8 ng/ml, and
approximately three-quarters of the men had a biopsy as a
consequence of an elevated PSA, half had no palpable tumor
(cT1c) and 70% had low-grade (Gleason ≤6) cancer on biopsy
– Median of 10 years of follow-up,
– 48% of the patients had died, but only 7% had died from
prostate cancer.
– There were no differences in overall or cancer-specific
mortality between the two arms of the trial.
– But there were clear indications that RP reduced the risk of
dying of cancer in the subset of men who had aggressive
cancers, including
• Those whose PSA was >10.0 ng/ml and
• Those with high-risk cancers

34. • two trials indicate that most men with cancers
detected without screening and those with
screen-detected intermediate- and high-risk
cancers have less risk of metastases and of
death from prostate cancer when treated with
early RP than with observation alone
• Men with screen-detected low-risk cancer can
be managed safely with AS and do not need
immediate surgery or radiotherapy.

35. • Management of Postoperative Biochemical
Recurrence
– Biochemical recurrence afterRP
• 50% of recurrences appear within 3 years
• 80% within 5 years
• 99% within 10 years
– Rarely, recurrences appear more than 15 years after
RP
– The PSA velocity or doubling time, the interval from
surgery to biochemical recurrence, and the Gleason
score usually reflect how rapidly the tumor is likely to
progress

36. • Adjuvant radiotherapy VS salvage
radiotherapy
– Radiotherapy administered proactively shortly
after surgery (after urinary continence has been
attained) in patients with undetectable PSA levels
is called adjuvant radiotherapy.
– In contrast, radiotherapy given selectively to men
with detectable postoperative PSA levels is called
salvage radiotherapy

37. • Adjuvant therapy should be strongly considered for patients with
Multiple or very high-risk tumor features—that is, extensive
extracapsular tumor extension, multiple or broad-based positive
surgical margins, seminal vesicle invasion, and lymph node
metastases.
• For patients with focally positive margins or minimal extracapsular
tumor extension, monitoring PSA every 4 months with early salvage
therapy being initiated when the PSA reaches 0.2 ng/ mL and is
verified to be rising may be more appropriate.
• In patients with a limited life expectancy, and especially those with
Gleason grade 6 or 7 tumors, PSA levels may be monitored to
measure the PSA velocity to help determine whether salvage
radiotherapy is necessary
Cotter et al, 2011; Karlin et al, 2013

38. Radiotherapy for Localized Prostate Cancer
• External beam or brachytherapy techniques is
a second treatment option for men with
clinically localized prostate cancers
• Intensity-modulated external beam
radiotherapy (IMRT) has become a standard
mode of treatment delivery
• Brachytherapy using permanent or temporary
radioactive implants within the prostate alone
or combined with IMRT

39. • High-dose IMRT alone (in the range of 80 Gy) or
brachytherapy alone are excellent treatment
options
– Patients with low-risk disease in whom AS may not be
considered—owing to PSA velocity, the presence of a
dominant lesion on imaging studies, or a larger
volume of disease determined by biopsy
• Larger prostate volumes, the presence of urinary
obstructive symptoms, and medical co
morbidities – brachytherapy is contraindicated

40. • For patients with intermediate- and higher-
risk disease, combined modality treatments
including brachytherapy and supplemental
IMRT are preferred to allow for the delivery of
a high and concentrated dose of radiation to
the prostate

41. • Intensity-Modulated Radiotherapy and Image-
Guided Techniques
– Clinical target volume (CTV) includes the entire
prostate gland and immediate periprostatic tissues, as
well as the seminal vesicles, as visualized on CT
– Low-risk disease with unremarkable imaging studies,
the CTV may exclude the seminal vesicles
– Use of image-guided approaches, the margin can be
safely reduced to 5 mm to 6 mm around the CTV,
except at the prostate-rectal interface, where an even
tighter margin (3 mm to 5 mm) is used

42. – 10% to 20% improvement in 5- to 10-year PSA survival
outcomes when higher doses of 78 Gy to 80 Gy are
applied, compared with dose levels of 70 Gy, and such
benefits have been observed for low-, intermediate-,
and high-risk cohorts
– For patients with intermediate- and especially high-
risk disease, doses beyond 80 Gy may be required to
achieve optimal tumor control outcomes
– Complication rates after EBRT
• Acute symptoms typically appear during the
third week of treatment
–Acute intestinal symptoms
–Internal and external hemorrhoids
–Acute urinary symptoms

43. • Late rectal toxicities
– 12 months to 18 months after completion of treatment
– Rectal bleeding, mucous discharge, and mild incontinence
of stool
– More-severe toxicities, including ulcer development and
fistula formation, are observed in ≤1% of patients
• Late urinary toxicities include chronic urethritis, which
occurs in approximately 10% to 15% of patients, and
urethral strictures, which occur in 2% to 3%.
Hemorrhagic cystitis
• Rates of impotence at 3 years or longer after EBRT
ranges widely from 36% to 68%,

44. • Hypofractionated External Beam Radiotherapy
– A pooled analysis of 1,100 patients treated from 2003 to
2011 at eight institutions
– The median dose delivered for these patients was 36.25 Gy
in five fractions.
– The median follow-up was 3 years;
– the 5-year PSA-relapse-free survival rates were 95%, 84%,
and 81% for low-, intermediate-, and high-risk patients,
repsectively.
– Stereotactic radiosurgery appears promising, but this form
of treatment cannot be considered an established form of
radiotherapy delivery, and ongoing studies will define its
role better in the years ahead.

45. • Role of Proton Therapy for Localized Prostate Cancer
• Bragg peak—by which the majority of the energy of
the beam is deposited at the end of its track, creating a
rapid falloff of dose beyond the target
• Proton therapy was associated with a lower risk of
erectile dysfunction
• No established evidence that proton therapy provides
superior tumor control outcomes, compared with well-
delivered high-dose IMRT or image-guided
radiotherapy, for the treatment of prostate cancer

46. • Prostate Brachytherapy
– Transperineal ultrasound-guided approaches
– Most commonly used radioisotopes for permanent seed
brachytherapy are iodine-125 (125I) and palladium-103
(103Pd)
– The half-life of 125I is 60 days, with a mean photon energy
of 27 KeV and an initial dose rate of 0.07 Gy/h
– Half-life of 103Pd is 17 days, with a mean photon energy of
21 KeV and an initial dose rate of 0.19 cGy/h.
– The active periods for 125I and 103Pd are 10 months and 3
months, respectively.
– 125I is used, the typical prescription dose is 144 Gy; 125 Gy
is routinely used for 103Pd.

47. Prostate Brachytherapy
• The size of the prostate gland should preferably be <60
cm3 and optimally <50 cm3
• The size of the prostate can be effectively addressed
with combined androgen-blockade therapy
• More suitable intervention for patients with
– Bilateral hip replacements
– Patients with small bowel in close proximity to the prostate
volume are also better suited to brachytherapy, owing to
the lower doses to the bowel expected with brachytherapy
– History of inflammatory bowel disease

48. • Brachytherapy is seldom used for the treatment of
high-volume, high-risk prostate cancers, because IMRT
is the preferred method for treatment of aggressive
tumors
• Proctitis and rectal injury are less common with
brachytherapy than with external beam therapy, but
erectile dysfunction occurs more commonly with
brachytherapy than with external beam radiation.
• Other complications associated with brachytherapy
include seed migration and rectourethral fistula

49. • Combined Brachytherapy and External Beam
Radiotherapy
– Increased dose of radiation that has been estimated
to have a biologic equivalent that well exceeds a 100-
Gy dose of EBRT
– Brachytherapy combined with IMRT boost was
associated with better PSA-relapse-free survival
(hazard ratio [HR] = 0.40; 95% CI = 0.24 to 0.66; p
<0.001) and better distant metastases–free survival
(HR = 0.41 [0.18 to 0.92]; p = 0.03)
– Late toxicity outcomes were 4.6% versus 4.1% for
grade 2 GI toxicity (p = 0.89), 0.4% versus 1.4% for
grade 3 GI toxicity (p = 0.36), 19.4% versus 21.2% for
grade 2 genitourinary toxicity (p = 0.14), and 3.1%
versus 1.4% for grade 3 genitourinary toxicity (p =
0.74) for the IMRT versus the combination RT groups,
respectively

50. • High-Dose-Rate Brachytherapy
– Ultrasound-guided transperineal placement of afterloading
catheters in the prostate
– High-dose fractions, ranging from 4 Gy to 6 Gy each, are
administered during an interval of 24 hours to 36 hours
using 192Ir
– Advantage of an afterloading approach, the
• Radiation oncologist and physicist can more easily
optimize the delivery of radiotherapy
• Reduces radiation exposure to the radiation oncologist
and others involved in the procedure
• Reduces radiation exposure to the radiation oncologist
and others involved in the procedure

51. • Optimal Radiotherapeutic Approach for Localized
Disease
– Low-risk disease - brachytherapy as monotherapy or IMRT
at dose levels of 80 Gy would be appropriate and
associated with biochemical outcomes of approximately
90% at 10 years
• Patients with enlarged prostate glands of 60 ml to 90 ml are best
treated with ADT to reduce the size of the gland before
brachytherapy
– intermediate- or high-risk disease, doses higher than 80 Gy
may be necessary
• Recommend for these patients brachytherapy in combination with
image-guided EBRT
• .

52. • ADT is used as adjuvant therapy
– Improve local eradication of locally advanced tumors by
reducing tumor size,
– Eliminate tumor clonogens inherently resistant to
radiotherapy by impairing DNA repair pathways, and/or
– Reducing prostate volumes by 30% to 40%, which
improves the ability to deliver maximal radiation dose
levels without exceeding the tolerance for the surrounding
normal tissue.
– Hormone therapy also has a favorable effect on
micrometastatic disease that may be present at the time of
diagnosis in men with high-risk tumors

53. • EORTC 22863
– Node-negative patients with clinical stage T3 disease
or T1–T2 patients with high-grade disease received
adjuvant ADT on the first day of radiotherapy
(prescribed dose of 70 Gy) and continued for 3 years
– 10-year overall survival was 58% versus 40% for
patients treated with ADT plus EBRT and EBRT alone,
respectively (p = 0.0004)
– 10-year PCSM rates for these respective cohorts of
patients were 10% and 30% (p <0.0001)

54. • Duration of ADT was addressed in RTOG 92-02
– Neoadjuvant and concurrent ADT for a total of 4
months or the same therapy plus an additional 24
months of adjuvant ADT for a total of 28 months
– At a median follow-up of 5.8 years, the results showed
that all outcomes were improved for patients who
received 28 months with the exception of overall
survival
– subset analysis, however, showed a 10% overall
survival advantage for patients with Gleason scores of
8 to 10 who were treated with the longer course of
ADT

55. • RTOG 94-13 evaluated two sequencing regimens
of adjuvant ADT
– Patients were randomized to receive either 4 months
of ADT before and during radiotherapy or 4 months of
ADT as adjuvant therapy following the completion of
EBRT
– Neoadjuvant and concurrent ADT in conjunction with
whole-pelvic radiotherapy was associated with a trend
for an improved progressionfree survival (PFS)
compared to the other study arms (48% PFS for
neoadjuvant ADT and whole-pelvic radiotherapy
versus 40% for prostate only radiotherapy and
adjuvant ADT; p = 0.065)

60. • Management of the Patient with Rising Prostate-
Specific Antigen After Definitive Local Therapy
– Biochemical failure after surgery is a detectable or rising
PSA level >0.2 ng/ml, with a second confirmatory increase
>0.2 ng/m
– Defining biochemical failure following radiotherapy with or
without hormonal therapy in men with clinically localized
prostate cancer: recommendations of the RTOG-ASTRO
Phoenix Consensus Conference.
• Prostate specific antigen (PSA) failure as occurring
after three consecutive PSA rises after a nadir with
the date of failure as the point halfway between
the nadir date and the first rise or any rise great
enough to provoke initiation of therapy
• Rise by 2 ng/mL or more above the nadir PSA be
considered the standard definition for biochemical
failure after EBRT with or without HT

61. • Salvage Radiotherapy for the Patient with Rising Prostate-
Specific Antigen After Prostatectomy
– Improved outcomes are achieved with salvage radiotherapy
when preradiotherapy PSA values are ≤0.5 ng/ml
– MSKCC, 285 patients with increasing PSA levels after
prostatectomy - treated with either salvage three-dimensional
CRT or IMRT
• The 7-year (median follow-up, 5 years) PSA-relapse-free
survival and distant metastases–free survival rates were 37%
and 77%, respectively
• Patients treated without any adverse prognostic features
had a 5- year PSA-relapse-free survival of 70%, compared
with 30% for those with any adverse feature
– Efficacy of salvage EBRT alone for clinically palpable local
disease or imaging evidence of disease within the prostatic bed
is suboptimal
– ADT can be used to improve local tumor eradication by reducing
the size of a mass, by the concurrent elimination of tumor
clonogens inherently resistant to radiotherapy, or both.

62. • Salvage Therapy for Locally Recurrent Disease After
Radiation
– Salvage RP, brachytherapy, or cryosurgery
– Patient selection requires a performance status of 80 or more,
histologic confirmation of disease in the gland, and no evidence
of metastatic disease by imaging
– Salvage Cryotherapy
• With the development of second- and third-generation
probes, real-time TRUS for intraoperative monitoring,
thermocouplers, and urethral warmers, cryotherapy is
potentially less toxic
• Case selection criteria include a prostate volume between 20
g to 30 g
• Biochemical disease-free survival rates range from 34% to
98%
• Reported long-term complications include erectile
dysfunction (77% to 100%), rectal pain (10% to 40%), urinary
incontinence (4% to 20%), urinary retention (0% to 7%), and
urethral sloughing (0% to 5%).302–307 Rectourethral
fistulas, the most serious complication following
cryotherapy, are relatively uncommon (0% to 4%)

66. Advanced Prostate Cancer
• Principle of treatment of advanced prostate
cancer is to deplete androgens or inhibit
signaling through the androgen receptor (AR)
• 1940s by Huggins and Hodges showed that
surgical removal of the testes or the
administration of exogenous estrogen could
induce tumor regressions, reduce the level of
acid phosphatase in the blood, and palliate
symptoms of the disease

69. • Noncastrate Prostate Cancer (Rising Prostate-
Specific Antigen and Noncastrate Metastases)
– Bilateral orchiectomy is an inexpensive standard
treatment that reliably reduces testosterone levels to
the “castrate” range (<50 ng/dl)
– Estrogens inhibit the production of LHRH, which
decreases the release of follicle-stimulating hormone
and LH, and reduces androgen levels in a dose-
dependent manner. A dose of diethylstilbesterol
(DES), 3 mg/d, generally achieves castrate
testosterone levels.

70. • LHRH agonists produce an initial rise in LH that
increases testosterone levels, followed 1 to 2
weeks later by downregulation of LH receptors
that results in a medical castration
– The initial rise in testosterone can flare the disease,
precipitating or exacerbating symptoms such as pain,
obstructive uropathies, and spinal cord compromise
• LHRH antagonists produce castrate levels of
testosterone in 48 hours without the initial rise
– Initial treatment of patients with symptoms

71. • Antiandrogens
– Block the binding of testosterone to the AR
– Steroidal type I agents - cyproterone acetate have
progestational properties that suppress LH levels
and lower serum testosterone; these are not
widely used.
– The nonsteroidal type II agents bind to the AR and
act as competitive antagonists for ligands.
– The three first-generation type II agents approved
are
• Flutamide - short half-life requiring multiple daily doses,
and
• Bicalutamide and nilutamide - weekly half-lives and are
administered once daily.

72. – All three were approved initially in combination with a
LHRH analog:
– Flutamide to prevent the flare that can result from the
initial rise in testosterone that occurs with LHRH analogs,
bicalutamide (50 mg daily) on the basis of an improved
safety profile relative to flutamide
– Nilutamide in combination with surgical orchiectomy
based on greater efficacy relative to orchiectomy alone
– Type II agents given as monotherapy do not inhibit LH
synthesis in the hypothalamus or pituitary, and circulating
testosterone levels rise.
– None of these antiandrogens are approved as
monotherapy in the United States, although bicalutamide
150 mg is approved in the European Union

73. • Enzymatic Inhibitors of Androgen Synthesis
– Ketoconazole
• Nonspecific P450 inhibitor that
• Dose of 1,200 mg/d,
• Produces castrate levels of testosterone in 24 hours through
inhibition of adrenal and testicular steroidogenesis
• The effect is not durable, limiting the drug’s use as first-line
treatment.
• It was useful for patients who presented with acute spinal
cord compression or disseminated intravascular coagulation,
when LHRH analogs are contraindicated and the risk of
hemorrhage from surgery is significant

74. • In a meta-analysis of 10 randomized controlled
trials that included LHRH agonists/antagonists,
orchiectomy, DES, or choice of DES or
orchiectomy, outcomes were similar.
• 27 randomized trials with 8,275 patients, showed
a 2% difference in mortality at 5 years: 72.4% for
monotherapy versus 70.4% for the combined
approach; a second meta-analysis limited to trials
of a nonsteroidal antiandrogen showed a 2.9%
difference: 75.3% versus 72.4% at 5 years. None
proved meaningfully superior

75. • The Veterans Administration Research Service
Cooperative Urological Research Group trials
enrolled 1,900 patients staged primarily by
DRE
– DES or orchiectomy could delay the development
of metastatic disease in patients with locally
advanced tumors, although overall survival was
worse due to cardiovascular complications.
– There was also no overall survival benefit for
patients with metastatic disease

76. • MRC PR03 trial randomized 998 patients
– Patients treated with early therapy were less likely
to require a TURP or develop ureteral obstruction,
progress from M0 to M1 disease (P <0.001, two-
tailed), to develop pain (P <0.001), or to die of
prostate cancer relative to those in whom therapy
was “deferred.” Even so, survival times were
similar between the two groups

77. • Toxicities of Androgen Deprivation Therapy
– Androgen deprivation syndrome include hot flashes, a
decrease in libido, erectile dysfunction, impotence,
fatigue, anemia, weight gain and alterations in fat
metabolism, loss of muscle mass and weakness, bone loss,
a decrease in mental acuity, mood swings, personality
changes, memory loss, depression, and insomnia
– Many of the adverse effects of ADT can be relieved by
exercise
– Hot flashes
• Occur in more than 80% of patients at any time, even during sleep,
and may last for several seconds or an hour or more.
• They are bothersome in about 25% of cases
• If significant, can be reduced in frequency and intensity with
estrogens at doses as low as 0.3 mg/d by patch or progestins (e.g.,
megestrol acetate or medroxyprogesterone acetate)

79. • Androgen deprivation is one of the most effective therapies against any
solid tumor; unfortunately, with time almost all prostate cancers will
become androgen refractory.
• All current forms of androgen deprivation therapy (ADT) function by either
lowering levels of circulating androgens or blocking the binding of
androgen to the androgen receptor.
• Almost all castration-resistant prostate cancer remains sensitive to
androgen; therefore ADT should continue in castration-resistant disease.
• Relative to testosterone and dihydrotestosterone, the adrenal androgens
are weak.
• There are four general forms of ADT: (1) ablation of androgen sources, (2)
antiandrogens, (3) inhibition of LHRH and/or LH, and (4) inhibition of
androgen synthesis.
• Bilateral orchiectomy reduces testosterone by 90% within 24 hours of
surgery.
• Nonsteroidal antiandrogens cause LH and testosterone levels to increase.
• Serious liver toxicity is a possible side effect of all antiandrogens.
• Antiandrogens can act as agonists on some tumors; antiandrogen
withdrawal results in PSA declines in 15% to 30% of patients.
• Bicalutamide 150 mg monotherapy appears to have equivalent efficacy to
medical or surgical castration for locally advanced or metastatic prostate
cancer.
• Enzalutamide improves overall survival in metastatic, castration-resistant
prostate cancer after treatment with chemotherapy

80.  Abiraterone improves overall survival in metastatic, castrationresistant prostate
cancer both before and after treatment with chemotherapy.
• All LHRH agonists induce a testosterone increase upon initial exposure.
Coadministration of an antiandrogen functionally blocks the effects of
testosterone.
• The magnitude and rapidity of the initial response to ADT are strong predictors of
the durability of that response.
• The side effects of ADT include osteoporosis, hot flashes, sexual dysfunction,
cognitive function alterations, changes in body habitus, gynecomastia, and
anemia. These side effects can be
progressive but are responsive to other treatments.
• There is no evidence that 3 months of neoadjuvant ADT prior to radical
prostatectomy improves biochemical outcomes.
• There is considerable evidence that ADT combined with external beam radiation
therapy improves overall survival, cancerspecific survival, and freedom from
disease progression. The optimal timing and duration of ADT in this combination
remains undefined.

81. • Based on a large meta-analysis of many clinical trials,
combined androgen blockade with nonsteroidal
antiandrogens provides about a 3% survival benefit at 5
years compared to standard ADT.
• The natural history of prostate cancer progression is
protracted. Many men with evidence of disease will never
require ADT.
• The use of ADT in low-risk, localized prostate cancer
increases overall (non–prostate cancer) mortality.
• In lymph node metastatic prostate cancer, ADT improves
overall survival if the primary tumor is removed but has no
significant effect if the primary tumor is not removed

82. • Follow-up after hormonal therapy
• Patients should first be evaluated at 3 and 6
mo after the initiation of treatment
• As a minimum, tests should include serum PSA
measurement, DRE, serum testosterone, and
careful evaluation of symptoms to assess
treatment response and side effects.

84. Castration-Resistant Prostate Cancer
• Castrate serum levels of testosterone (testosterone <50
ng/dl or <1.7 nmol/l).
• Three consecutive rises of prostate-specific antigen (PSA), 1
wk apart, resulting in two 50% increases over the nadir
with PSA >2.0 ng/ml.
• Antiandrogen withdrawal for at least 4 wk for flutamide and
for at least 6 wk for bicalutamide.
• PSA progression, despite consecutive hormonal
manipulations.
• Progression of osseous lesions: progression or appearance
of two or more lesions on bone scan or soft tissue lesions
using Response Evaluation Criteria in Solid Tumours and
with nodes >2cm in diameter.

86. • Nonmetastatic Castration-Resistant Prostate
Cancer
– At present there is no consensus regarding the
most appropriate management for patients with
nonmetastatic CRPC
– Sequential endocrine approach (using second-
generation agents, e.g., ketoconazole) is the most
commonly used therapeutic modality.

87. Metastatic Castration-Resistant Prostate Cancer
• Cytotoxic Chemotherapy
– Docetaxel is the standard first-line chemotherapy for
mCRPC. It prolongs progression-free and overall
survival, ameliorates pain, and improves quality of
life.
– Toxicity of docetaxel includes myelosuppression,
fatigue, peripheral edema, neurotoxicity,
hyperlacrimation, and nail dystrophy.

88. • TAX 327
– From March 2000 through June 2002,
– 1006 men with metastatic hormone-refractory prostate
cancer received 5 mg of prednisone twice daily and were
randomly assigned to receive
• 12 mg of mitoxantrone per square meter of body-surface area
every three weeks,
• 75 mg of docetaxel per square meter every three weeks, or
• 30 mg of docetaxel per square meter weekly for five of every six
weeks
– The median survival was 16.5 months in the mitoxantrone
group, 18.9 months in the group given docetaxel every 3
weeks, and 17.4 months in the group given weekly
docetaxel
– When given with prednisone, treatment with docetaxel
every three weeks led to superior survival and improved
rates of response in terms of pain, serum PSA level, and
quality of life, as compared with mitoxantrone plus
prednisone.

89. – Cabazitaxel has emerged as a second-line
chemotherapy option for patients with mCRPC
who have had progressive disease during or after
docetaxel treatment.
– Novel tubulin-binding taxane
– Poor affinity for P-glycoprotein, the adenosine
triphosphate–dependent drug efflux pump
– Toxicity of cabazitaxel includes neutropenia
(including febrile neutropenia) and diarrhea

90. • Pivotal randomized phase III (TROPIC) trial
– Conducted in 146 institutions across 26 countries, which
recruited 755 men with mCRPC who had progressed after
docetaxel-based chemotherapy
– 377 patients were randomized to receive mitoxantrone 12
mg/m2 intravenously every 3 weeks (with oral prednisone
10 mg daily), and 378 patients were assigned to receive
cabazitaxel 25 mg/m2 intravenously every 3 weeks (plus
prednisone)
– After a median follow-up of 12.8 months, overall survival
in men receiving cabazitaxel was 15.1 months compared to
12.7 months in men receiving mitoxantrone (HR 0.70, P <
.0001)

91. • Although it does not prolong survival, mitoxantrone
has been approved to palliate symptoms associated
with metastatic disease, and it is often used in
patients who have previously received docetaxel
and/or cabazitaxel, or in those who would not
tolerate these agents.

92. • ANDROGEN RECEPTOR– DIRECTED APPROACHES
– There is mounting evidence that CRPC is not
androgenindependent and continues to rely on androgen/AR
signaling.
– Abiraterone is a CYP17 inhibitor that depletes adrenal and
intratumoral androgens. It is approved for the treatment of
mCRPC, both before and after chemotherapy.
– Enzalutamide is a novel AR signaling inhibitor that blocks the AR
and prevents nuclear translocation and DNA binding. It was
shown to improve survival in men with mCRPC both in the
prechemotherapy and postchemotherapy settings.
– Additional CYP17-targeting agents (e.g., orteronel) and AR-
targeting agents (e.g., ARN-509) are in clinical development.

93. • IMMUNOTHERAPY
– Sipuleucel-T is the first therapeutic vaccine to be approved by
the FDA for the treatment of any cancer, and it is indicated for
men with asymptomatic or minimally symptomatic mCRPC
without visceral metastases or cancer-related pain requiring
narcotics.
– ProstVac-VF is a poxviral-based PSA-directed prostate cancer
vaccine that is administered by subcutaneous injection. It is
currently in phase III testing for men with asymptomatic or
minimally symptomatic mCRPC.
– Ipilimumab shows promising clinical activity in men with
mCRPC, although a large trial in docetaxel-pretreated patients
narrowly missed its primary survival end point. Although
ipilimumab is not currently FDA-approved for prostate cancer,
an ongoing trial is evaluating ipilimumab in men with mCRPC
who have not yet received chemotherapy.
– The future of prostate cancer immunotherapies is likely to
involve their use in the early-disease setting, or in combination
with other standard prostate cancer therapeutics (hormone
therapy and radiotherapy).

94. • NOVEL TARGETED TREATMENTS
– Despite negative studies with bevacizumab and aflibercept,
angiogenesis remains a valid therapeutic target in prostate
cancer, as exemplified by the novel agent tasquinimod.
– Because of the reciprocal interactions between the PI3K/Akt/
mTOR pathway and the AR signaling pathway, dual inhibition of
both pathways concurrently will likely represent the most
fruitful therapeutic strategy.
– Cabozantinib is a novel small molecule inhibitor of c-Met and
VEGFR2, with profound activity on CRPC bone metastases.
– Custirsen is an antisense oligonucleotide against clusterin
mRNA, which may play a role in reversing resistance to taxane
chemotherapies

96. • PALLIATIVE MANAGEMENT
– Patients with back pain and a history of bone metastases should
be evaluated for epidural cord compression. The clinical
syndrome often includes at least one of the following signs and
symptoms: back pain, focal neurologic deficit (leg weakness,
sensory levels), or changes in bladder or bowel control.
– Initial management of suspected cord compression includes
immediate MRI of the spine and initiation of high-dose
intravenous corticosteroid therapy. Definitive treatment should
include radiation therapy, surgical decompression, or both.
– Zoledronic acid and denosumab are both reasonable treatment
options for the prevention of skeletal-related events in patients
with castration-resistant bone metastases. Denosumab may
include the advantage of not requiring renal dosing. Both agents
can (rarely) cause ONJ.
– Radium-223 is a novel alpha-emitting radiopharmaceutical that
the FDA has approved for the treatment of symptomatic bone
metastases in CRPC patients without visceral metastases or
bulky lymph node disease. The recommended dose is 50 kBq/kg
intravenously every 4 weeks for a total of 6 cycles.

97. THE NEUROENDOCRINE/ANAPLASTIC PHENOTYPE

98. • These tumors are invariably unresponsive to
hormonal manipulations but are transiently
sensitive to radiation therapy and
chemotherapy including platinum-etoposide
combinations (or platinum-docetaxel
combinations).