Prostate Cancer Summary
Epidemiology:
·
29% of all newly diagnosed
cancer in males and 11% of cancer related deaths in 2011.
·
7:1 ratio of incidence to
mortality
·
Autopsy series show that
nearly 70% of men older than age 80 have occult prostate cancer
·
Individuals with 1 first
degree relative diagnosed with prostate cancer have a 2 fold increased lifetime
risk, which increases to 4- fold if 2 or more relatives are affected before age
70.
·
5-10% of all cases are
hereditary and follow a Mendelian inheritance pattern.
·
High consumption of dietary
fats, in particular the fatty acid alpha-linoleic acid, is believed to increase
risk by 2-3 fold
·
Until a patient has CRPC,
he is unlikely to do die of his illness
Anatomy:
·
The peripheral zone is
palpable by DRE and is the site of origin of 70% of cancers.
·
The transition zone
surrounds the urethra and can’t be assessed by DRE. Up to 20% of all cancer
will develop in the transition zone, however BPH is more common that prostate
ca in this area
Pathology:
·
50% of patients with PIN
(prostate intraepithelial neoplasia) will have cancer in 5 yrs.
·
99% of prostate cancers are
adenocarcinomas; < 1% are pure ductal and mucinous variants
·
Urothelial carcinomas of
the prostate are confined to the periurethral ducts and are more common among
patients who have been successfully treated for noninvasive bladder cancer.
·
Lymphomas and leukemias may
also occur in the prostate gland
·
The Gleason grading system:
o
Describes the morphology of
adenocarcinomas
o
Score of 1 to 5 for the
primary and secondary growth patterns within the tumor
·
Androgens are the primary
regulators of prostate cancer cell growth and proliferation
·
The development of prostate
cancer involves a multistep process in which androgen receptor signaling plays
a key role.
·
Gene expression profiling
has identified numerous molecular abnormalities that may differ between
primary, metastatic and CRPC:
o
The frequency of expression
of HER2 and BCL-2 is higher in castrate metastatic lesions than untreated
localized tumors
o
Potential molecular targets
that have undergone clinical investigation include HER2, BCL-2, VEGF, Src, the
endothelin receptor, interleukin-6 and prostate specific membrane antigen.
Tumor staging:
·
T1c is the most frequent
classification at the time of diagnosis (tumor identified by needle biopsy on
the basis of elevated PSA and no palpable disease b DRE).
·
T3 is the tumor extends
through the prostate capsule
·
If you have lymph node
involvement it is considered stage IV disease
Prevention:
·
The Prostate cancer
prevention trial (PCPT):
o
Randomized, multicenter,
double blind study
o
Enrolled total of 1800 men
o
Half patients received 5 mg
of Finasteride daily for 7 yrs and other half received Placebo.
o
24.8% reduction in prostate
cancer risk among men treated with Finasteride, with higher frequency of high
grade lesions for this same group.
·
The reduction by
Dutasteride of prostate cancer events (REDUCE) trial:
o
High risk men
o
Patients received 0.5
mg/day of Dutasteride or Placebo for 4 years
o
23% risk reduction.
Subgroup analysis consistently favored Dutasteride regardless age, family
history, PSA level
·
The FDA confirmed a
relative reduction of approximately 25% in the overall incidence of prostate
cancer but also a significantly increased incidence of high grade prostate
cancer. The final conclusion is that these drugs do not have a favorable risk
benefit profile for chemoprevention.
·
The Physicians Health
Study II:
o
Trial of vitamin E & C in
14,641 male physicians in the USA age 50 or older
o
It didn’t reduce the risk
of prostate cancer
·
The SELECT trial:
o
Evaluated 35,553 men in
double-blind 2x2 study of selenium and vitamin E alone and in combination
o
No significant difference
in the development of prostate cancer
o
At 7 yrs there is 17%
increase risk of prostate cancer in vitamin E group (400 IU daily while the
daily requirement is only 22.4 IU).
·
Prospective randomized
trials have not convincingly proven that PSA screening decreases mortality.
Diagnosis:
·
PSA :
o
Single chain glycoprotein
o
Prostate specific but not
cancer specific. (elevated in BPH, prostatitis, after biopsy and ejaculation)
o
DRE doesn’t alter the PSA
level
o
Half life of PSA is 2-3
days and levels should remain undetectable if the prostate has been removed.
o
The prevalence of cancer
was 6.6% with PSA up to 0.5 ng/ml, 10.1% with PSA between 0.6-1 ng/ml, 17% with
PSA between 1.1-2 ng/ml, 23.9% with PSA between 2.1-3 ng/ml, and 26.9% with PSA
between 3.1-4 ng/dl.
o
Men with annual PSA <
4.0 ng/ml should be referred for evaluation if the absolute numeric change over
12 months (PSA velocity) is at least 0.35 ng/ml per year.
o
For men with PSA value
between 4 ng/ml and 10 ng/ml, a PSA velocity of at least 0.75 ng/ml per year is
suspicious for cancer.
·
The diagnosis of prostate
cancer in established with a TRUS guided needle biopsy using a biopsy gun. An
extended pattern 12 core biopsy is recommended.
·
Free PSA is not generally
recommended to determine whether to perform a prostate biopsy
·
Pelvic CT or MRI scans are
recommended if the tumor is T3, T4.
·
The Yield of bone scan is
low for patients with tumors that are T2 or less, Gleason score of < 7, and
PSA level of < 10 ng/ml.
·
Bone scan is
recommended if T1,2 and PSA >20
ng/ml, Gleason score of 8, T3,4 or symptoms of bone metastasis
·
Patients with rising PSA
and no detectable metastasis on scans after radical prostatectomy or radiation
therapy usually have median time to the detection of metastasis of 8 yrs, and
63% will remain free of metastasis at 5 yrs.
Management:
·
Treatment for tumors confined to the prostate:
o
Low risk localized:
§
Active surveillance
§
Brachytherapy
§
External beam radiation
therapy
§
Radical prostatectomy
o
Intermediate and high
risk localized:
§
Combined modality
o
Radical prostatectomy:
§
92 % have complete
continence at 1 yr
§
Preservation of both
neurovascular bundles causes erectile function to return in a median of 4-6
months.
§
Sacrificing one nerve
bundle decreases recovery by 50%
o
Radiation therapy:
§
Higher frequency of bowel
complications, mainly diarrhea and loose stools than surgery
§
An acute toxicity of
implantation is irritative urinary symptoms
§
4 prospective randomized
trials have demonstrated that radiotherapy doses < 70 Gy are inadequate for
curative treatment. It is not clear if exceeding 78Gy to 78 gy render
additional benefits
§
The relative efficacy of
external beam radiation therapy compared with permanent prostate implants
remains controversial.
o
JCO; 2005;23(32):8178
·
Cryosurgical ablation
and high intensity focused ultrasound are considered for patients who are
not suitable for radical surgery or who have local recurrences. Sufficient long
term follow up is lacking to estimate efficacy.
·
Neoadjuvant and adjuvant
ADT:
§
Neoadjuvant ADT before
surgery leads to a reduction n the rate of positive surgical margins; it has
not had an effect on OS and is not recommended.
§
The benefit of immediate
adjuvant ADT after surgery in men with localized disease at high risk for
relapse is not proven.
§
Multiple randomized trials
showed that neoadjuvant and concurrent ADT is beneficial for intermediate risk
patients receiving external beam radiation therapy with an optimal duration of
3-4 months. (N Engl J Med. 2011; 365: 107-118.)
§
Although 6 months of ADT
was associated with a longer time to PSA recurrence and decreases mortality for
men with a pretreatment PSA velocity >2 ng/ml/yr. (J Clin Oncol. 2006; 24:
4190-4195.)
§
Patients with high risk
disease should receive long term adjuvant ADT for at least 2 yrs. (N Engl J
Med. 2009; 360: 2516-2527.)
§
The role of immediate long
term ADT in pathologically documented LN +ve is supported by subset analysis in
the RTOG 8531. LN +ve pts assigned to immediate ADT + RT had significantly
improved outcomes (OS, metastatic risk, local recurrence. PSA control) compared
to RT alone. JCO 2005; 23; 800.
§
In a study of patients
undergoing radical prostatectomy, patients with LN +ve disease after surgery
randomly assigned to ADT vs observation. Those who had immediate ADT had
significant improvement in PFS, OS and cancer specific survival. (Lancet Oncol.
2006;7:472)
·
Watchful waiting and
active surveillance:
§
Usually for older men with
well differentiated tumors in whom tumor progression occur over long period of
time and substantial proportion of them die of inter-current disease.
§
A structured literature
review showed that 10 yr mean weighted survivals were 93% for radical
prostatectomy, 84% for deferred approach and 74% for external beam radiation.
§
A retrospective cohort
study using the Connecticut tumor registry showed that the 20 yr prostate
cancer specific survival for men with Gleason score < 6 treated with
watchful waiting was 80-90%
§
Retrospective study of
44,630 men ages 65-80 diagnosed bet. 1991-1999 with organ-confined, well to
moderately diff. ca stratified as having receiving treatment or observation
found a statistically significant survival advantage associated with treatment
(HR 0.69, 95% CI 0.66-0.72) in all subgroups examined including older men (age
75-80), black men and men with low risk disease.
§
A prospective trial of 695 men randomly
assigned to watchful waiting or radical prostatectomy, death from prostate ca
after 15 yrs follow up was 21.7% in surgery group and 33.4% in watchful group
(statistically significant). HOWEVER the mean PSA in the observation group was
12.3 ng/ml and 74% had T2 lesions which make these results unlikely to apply
for the current US population where nearly half new cases are diagnosed with
T1c lesions.
§
This approach showed be
offered to patients with: (Gleason score < 6, PSA < 10 ng/ml, T1c-2a
lesions)
§
Patients should be
monitored by serial PSA, DRE & periodic prostate biopsy every 1-2 yrs.
· Local Failure:
o
A local recurrence is more
likely if:
§ PSA became detectable >1 yr after surgery
§ PSA doubling time > 10 months
§ Radical prostatectomy specimen contained low Gleason score <
7 & there was no seminal vesicle invasion or LN mets.
o
Retrospective study
demonstrated that salvage radiotherapy alone was associated with a significant
3 fold increase in prostate cancer specific survival relative to those who
didn’t receive salvage therapy. This benefit was limited to men with a PSA
doubling time < 6 months
o
3 prospective randomized
trials suggested that immediate postoperative radiotherapy in men with advanced
pathologic features (stage pT3a, pT3b) and or positive surgical margins
improves biochemical PFS but no improvement in OS. (Int J radiat Oncol Biol
Phys. 2008;72;972)
o
Patients treated initially
with radiation therapy may be considered for salvage prostatectomy if they were
surgical candidates at the time of diagnosis, have a life expectancy of > 10
yrs.
·
Hormonal therapy:
o
ADT can be divided into
§ Drugs that lower the Testosterone levels as GnRH agonists,
antagonists & estrogen
§ Drugs don’t lower the level but blocks the androgen action at
the level of the androgen receptors as anti-androgens.
o
Castration is associated
with gynecomastia, impotence, and loss of libido, weakness, fatigue, hot
flushes, loss of muscle masses, and change in personality, anemia, depression
and loss of bone mass over time.
o
Prolonged time on ADT that
lowers testosterone can result in osteoporosis. It also causes metabolic
complications as insulin resistence, hyperglycemia and metabolic syndrome,
which may be responsible for an increased risk of cardiovascular mortality.
o
The Denosumab Hormone
Ablation Bone Loss Trial ( HALT):
§ 60 mg of Denosumab SubQ every 6 months in men receiving ADT for
non-metastatic prostate ca.
§ Patients either had a low bone mineral density (T score at the
lumbar spine, total hip, or femoral neck of less than −1.0) at baseline or a
history of an osteoporotic fracture.
§ 1568 pts were assigned to Denosumab or placebo
§ Bone density of lumbar spine increased by 5.6% in Denosumab
group at 24 months compared to 1% loss in placebo group.
§ Decreased incidence of new vertebral fracture at 36 months (1.5%
vs 3.9% with placebo)
§ In 2011 FDA approved the drug for that purpose.
·
ADT for metastatic prostate cancer:
o
Upon starting ADT you
should expect 60-70% of patients with abnormal PSA levels to normalize to <4
ng/ml, 30-50% of measurable tumor masses to regress by 50% or more, and
approximately 60% of patients will have palliation of symptoms.
o
Scintigraphic flare on
serial bone scans can occur following ADT between 3-6 months after initiation
of therapy; this should not be confused with progression of skeletal
metastasis.
o
In an analysis of survival
in more than 1000 patients treated with
ADT, the PSA value measured at 7 months after initiating therapy was predictive
of outcomes, with a median survival of 13 months for patients with a PSA nadir
of > 4 ng/ml, 44 months for patients with PSA nadir > 0.2 ng/ml < 4
ng/ml, and 75 months for patients with PSA nadir of < 0.2 ng/ml
o
The initial rise of
testosterone after treatment with a GnRH agonist can result in clinical flare
up of the disease. These agents are contraindicated as monotherapy for patients
with (severe pain, urinary symptoms, spinal cord compression). An antiandrogen
can be used with it to block the flare response or a GnRH anatagonist that
suppress testosterone without a testosterone surge can be used as initial
therapy.
o
In 2000, the Prostate
Cancer trialists’ Collaborative Group (PCTCG) published a meta-analysis of
combined androgen blockade showing that nonsteroidal antiandrogens conferred a
small but statistically significant improvement in 5 yr survival over
castration therapy alone (72.4% vs 75.3%; HR 0.92; p< 0.005). (Lancet. 2000;
355; 1491)
o
A phase III randomized
trial comparing combined androgen blockade using LHRH agonist and 80 mg of
Bicalutamide compared with LHRH agonist alone in patients with advanced
prostate cancer showed a significant
improvement in OS after a median of 5.2 yrs of follow up ( HR 0.78, 95% CI 0.60-0.99, p< 0.0498), although there was
no significant difference in cause specific survival. (Cancer 2009; 115; 3437)
o
Antiandrogens as
monotherapy are inferior to testosterone lowering therapy. (Eur Urol.
1998;33;447)
o
If the decision is made to
begin ADT in patients with rising PSA but no evidence of metastasis,
data suggests that intermittent ADT is a reasonable alternative to continuous
ADT.
§
Phase III non-inferiority
trial enrolled 1386 men with this problem after xRT (NEJM 2012;367: 895):
§
No difference in OS
§
Time to develop CRPC was
statistically significantly improved in the intermittent arm (HR 0.8)
§
Intermittent ADT had
reduced hot flushes but no other difference in toxicity.
o
Early vs Delayed ADT:
§ In a study conducted by the Medical Research council, 938
patients with locally advanced or asymptomatic metastatic disease were randomly
assigned to either immediate therapy (medical or surgical castration) or to
same treatment deferred until an indication occurred. Patients with early
treatment were less likely to have progression from Mo to M1, have pain and die
of prostate cancer. (Br J Urol. 1997;
79; 235)
·
Treatment of Castration resistant prostate cancer:
o
Patients who are taking an
antiandrogen are first given a trial of antiandrogen withdrawal based on the
observation that these agents, although initially providing benefit, can later
contribute to prostate cancer progression. Thereafter, a 2nd agent,
such as another antiandrogen, ketoconazole, or hydrocortisone, may be
considered. Responses when they occur are frequently of short duration (2-4
month median).
o
In 10-15% of patients,
disease will relapse with aggressive local or distant metastases, where the
level of PSA appears to be disproportionately low for the tumor burden present.
The results on repeat biopsy may indicate a neuroendocrine phenotype.
o
Immunotherapy
§ Sipuleucel-T (Provenge) is an autologous cellular vaccine
composed of prostatic acid phosphatase and granulocyte-macrophage
colony-stimulating factor. It is administered IV every 2 weeks for a total of 3
infusions designed to elicit an immune response to prostatic acid phosphatase.
§ Phase III, placebo controlled trial of men with minimally
symptomatic metastatic CRPC, patients who received Sipuleucel-T had a median OS
of 25.8 Months compared with 21.7 months in patients who received Placebo (HR
0.78, 95%CI 0.61-0.98, p=0.03). No significant effect on PSA values or PFS was
observed. At 3 yrs % of patients alive in both groups was 31.7% vs 21.7%. Based
on this study it was FDA approved in 2010. (Clin Cancer Res. 2011; 17; 4558)
o
Chemotherapy
§ TAX 327 trial:
·
Phase III randomized trial in
2004 of 1006 men with CRPC receiving 5 mg of prednisone BID compared
Docetaxel-based therapy to Mitoxantrone found a significant improvement in OS
in the Docetaxel arm.
N Engl J Med. 2004; 351; 1502
|
||||
OS
|
50% decrease in PSA
|
Reduction in pain
|
Improved quality of
life
|
|
Docetaxel 75mg/m2
q3wks
|
18.9 mths
|
45% of pts
|
35% of pts
|
22% of pts
|
Docetaxel 30mg/m2 5/6
wks
|
17.4 mths
|
48% of pts
|
31% of pts
|
23% of pts
|
Mitoxantrone 12mg/m2
q3wks
|
16.5 mths
|
32% of pts
|
22% of pts
|
13% of pts
|
§
An updated survival of the
TAX 327 trial was published in JCO 2008 and confirmed the survival benefit. JCO
2008; 26; 242.
§ SWOG 9916 trial:
·
Phase III randomized trial
in 2004 of 770 men with CRPC compared Docetaxel-based therapy to Mitoxantrone
and found a significant improvement in OS in the Docetaxel group.
N Engl J Med. 2004; 351; 1513
|
||||
OS
|
50% decrease in PSA
|
Time to progression
|
Objective tumor
response rate
|
|
Estramustine 280mg
TID day1-5, Docetaxel 60mg/m2 day 2 q3wks
|
17.5 mths
|
50% of pts
|
6.3 mths
|
17% of pts
|
Prednisone 5 mg bid, Mitoxantrone
12mg/m2 q3wks
|
15.6 mths
|
27% of pts
|
3.2 months
|
11% of pts
|
·
CALGB 90401 tested if
addition of Bevacizumab to Docetaxel and Prednisone prolonged survival.
There was no improvement in OS, although there was an improvement in PFS
·
The benefit of chemotherapy
for patients with non-metastatic CRPC has not been established.
·
TROPIC trial: Cabazitaxel was FDA approved as a
2nd line chemotherapy on the basis of a phase III randomized open
label trial of 755 men with mCRPC who had received previous hormone therapy, but
whose disease had progressed during or after treatment with a
docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily,
OS
|
HR
|
PFS
|
|
Cabazitaxel 25mg/m2 IV q3wks
|
15.1 mths
|
0.70
(95%CI 0.59-0.83)
P<0.0001
|
2.8 mths
|
Mitoxantrone 12mg/m2
IV q3wks
|
12.7 mths
|
1.4 mths
|
|
·
Grade 3-4 neutropenia was
the major serious toxicity in pts who received Cabazitaxel, suggesting that
primary prophylaxis with G-CSF should be considered.
·
Mitoxantrone and other
regimens that have demonstrated activity in CRPC may be beneficial as 3rd
line therapy for patients with a good performance.
·
In patients with
neuroendocrine or small cell histologies, the use of Platinum-containing
chemotherapy regimens such as Etoposide and Cisplatin may be beneficial.
o Targeted Therapies
·
Abiraterone acetate
is an oral CYP17 inhibitor that inhibits androgen biosynthesis. It can be used
in the pre and post- Docetaxel setting based on the following trials.
§ COU-AA-301 trial:
·
Phase III randomly assigned
in a 2:1 ration, 1195 pts who previously received Docetaxel to receive 5mg of
Prednisone BID with either 1000 mg of Abiraterone acetate daily (797 pts) or Placebo (398 pts).
·
OS was significantly longer
in Pts as well as PFS, PSA response rate and time to PSA progression
N Engl J Med. 2011;364;1995
|
|||||
OS
|
HR
|
PFS
|
Time to PSA
progression
|
PSA response rate
|
|
Abiraterone
acetate
|
14.8 mths
|
0.65
(95%CI 0.54-0.77)
P<0.001
|
5.6 mths
|
10.2 mths
|
29%
|
Placebo
|
10.9 mths
|
3.6 mths
|
6.6 mths
|
6%
|
|
·
COU-AA-302 trial:
§ Phase III double blinded randomly assigned 1088 pts to receive
Abiraterone acetate 1000 mg daily plus Prednisone 5mg BID or placebo plus
prednisone.
§ The study was unblended after a planned interim analysis that
was performed after 43% of the expected deaths had occurred.
§ There were improved radiographic PFS, trend toward improved OS,
significantly delayed clinical decline and initiation of chemotherapy.
N Engl J Med. 2013;368;138
|
|||||
OS
|
HR
|
Radiographic PFS
|
HR
|
Time to initiate
chemotherapy
|
|
Abiraterone
acetate + prednisone
|
Not reached
|
0.75
(95%CI 0.61-0.93)
P<0.01
|
16.5 mths
|
0.53 (95% CI
0.45-0.62) P< 0.001
|
25.2 mths
|
Placebo + Prednisone
|
27.2 mths
|
8.3 mths
|
16.8 mths
|
||
·
Main side effects of
Abiraterone are mineralocorticoid-related toxicities as fluid retention, HTN
& hypokalemia.
·
Enzalutamide is a
highly potent oral androgen receptor antagonist that blocks androgens from
binding to the androgen receptors. It is approved in the post-Docetaxel setting
in the basis of the following trial
§ AFFIRM Trial:
§ Phase III double blinded, placebo controlled tiral of 1199 men with mCRPC after chemotherapy randomized
in 2:1 ration to receive oral Enzalutamide at dose of 160 mg daily (800 pts) vs
placebo (399 pts).
§ The study was stopped after a planned interim analysis at the
time of 530 deaths.
§ There was significantly prolonged OS as well as improvement in
all 2ry endpoints (soft tissue response rate, quality of life, radiographic
PFS, time to PSA progression and proportion of pts with > 50% PSA reduction
as well as time to first skeletal related event.
N Engl J Med. 2012;367;1187
|
|||||
OS
|
HR
|
Radiographic PFS
|
Time to PSA
progression
|
% pts with PSA
reduction of 50%
|
|
Enzalutamide
|
18.4 mths
|
0.63
(95%CI 0.53-0.75)
|
8.3 mths
|
8.3 mths
|
54 %
|
Placebo
|
13.6 mths
|
2.9 mths
|
3 mths
|
2 %
|
|
§ PREVAIL
trial: (presented at the 2014 ASCO Genitourinary Cancers Symposium)
§ Phase
III double blinded, placebo controlled trial of 1717 men with asymptomatic or
mildly symptomatic chemotherapy-naïve mCRPC.
§ Randomized
1:1 to enzalutamide 160 mg/day or placebo.
§ The
interim analysis at 539 deaths showed a statistically significant benefit of
enzalutamide over placebo with a 30% reduction in risk of death (OS: HR 0.70;
95% CI: 0.59-0.83; P< 0.0001) and an 81% reduction in risk of radiographic
progression or death (rPFS: HR 0.19; 95% CI: 0.15-0.23; P< 0.0001).
·
The alpha emitter
radium-223 is a bone-seeking radionuclide
§ ALSYMPCA trial:
(NEJM; 2013; 369;213)
§ A phase III in 922 men with symptomatic metastatic CRPC who had
received Docetaxel were randomly assigned to radium-223 chloride or to placebo
every 4 weeks for up to 6 treatments.
§ The median OS was 14 months for men treated with radium-223 vs
11.2 for men treated with placebo. Toxicity was mild with anemia being the most
common hematologic toxicity.
·
Early studies with the dual
met-VEGFR tyrosine kinase inhibitor Cabozatinib have resulted in significant
pain relief and clinical as well as bone scan responses in pts with CRPC who
were heavily pre-treated. Multiple phase III trials are undergoing.
·
Treatment of bone
metastasis in mCRPC:
§ A phase III non-inferiority trial compared Denosumab with
Zoledronate administered every 4 weeks for the prevention of skeletal related
events in men with CRPC & bone mets.
§ The median time to first event was 20.7 months with Denosumab vs
17.1 months with Zoledronic acid. (HR 0.82, 95% CI 0.71-0.95, p= 0.0002 for
non-inferiority & p= 0.008 for superiority).
§ Hypocalcaemia was more common in pts treated with Denosumab
§ Osteonecrosis of the jaw occurred infrequently in both arms.
§
Either therapy is
recommended together with calcium and vitamin D.
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