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Management of locally advanced
& metastatic prostate cancer
Dr. Purvish. M. Parikh
MD, DNB, PhD, FICP
Professor & Head
Department of Medical Oncology
Tata Memorial Hospital
Prostate cancer
Epidemiology
•Most commonly diagnosed cancer in men after 50
•Life time risk -30% (microscopic)
•Risk of developing clinical disease -10%
• Incidence : 36% of all cancers in males
-316000 new cases diagnosed
-Mortality : 40000 deaths
# Incidence : 4.8 / 100000 pop / year (Chennai)
8.1 / 100000 pop / year (Mumbai)
32000 new cases in 1999
# 1% increase in incidence every year
Natural history
Locally advanced
prostate cancer
Locally advanced prostate cancer
Clinical staging
Clinical disease
AJCC
1997
AUA
stage
Extracapsular
extension (UL/BL)
T3a
C1
Seminal vesicle
invasion
T3b
C2
Tumor fixed or
invades adjacent
structures
T4
C2
Natural history of clinical T3 prostate
cancer
• Prostate cancer is inherently biologically
heterogenous
• Patients have been staged differently in
various studies
Stage
N
15 year PFS
15 year DSS
%
95% CI
%
95% CI
T1-T2
300
48
37.3-58.7
80.9
73.6-88.2
T3-T4
183
46.6
32.7-60.5
56.5
44.6-68.4
M+
159
6.2
0.8-10.6
5.7
-0.1-11.5
Johansson et al, JAMA,1997;227:467-471
Management options & Patterns of care
•
•
•
•
Radical prostatectomy – 15.8%
External beam radiotherapy – 34.3%
Cryosurgery
Combined modality treatments - 14.3%
– Radical prostatectomy + ADT
– External beam radiotherapy + ADT
• Systemic therapy
– Hormonal therapy – 20.2%
– Chemotherapy
• No cancer treatment – 15.5%
Jones et al J Am Coll Surg,1995;180:545-554
Results of RP in T3 tumors
•RP alone is unlikely to cure most men with cT3 disease
•Upto 50 % patients are found to have pelvic lymph node
metastases at staging lymphadenectomy
•RP may have a role in selected patients with
low/intermediate grade tumors
Study
N
Mean FU
(yrs)
Pathologic stage
Outcome
Zincke
1986
101
4.9
C-49,D1-52
LOR-17%
Bosch,
1987
48
3.6
C-25,D1-23
LOR-30%
Ouden,
1994
100
3.6
T3-39, T4-2,D1-48
pT3-38% LOR, 31 % BF
Lerner,
1995
812
4.5
T2c-17,T3-49,
D1-33
DSS@15 yr-69%
Results of EBRT in T3 tumors
• EBRT is less morbid & provides good local control & OS benefit
• Outcomes different in Pre-PSA & PSA era
• EBRT alone is unlikely to eradicate most locally advanced
prostate cancers
Results of conventional EBRT in T3 prostate cancer
Study
N
Local RFS (n)
OS (n)
5
10
15
5
10
15
Stanford,1993
409
76
63
40
68
38
20
POC,1994
216
70
65
60
56
32
23
MDACC, 1995
551
88
81
75
72
47
27
MSKCC,1993
412
72
60
-
65
42
-
Locally Advanced Prostate Cancer
Modifications in Radiation Therapy
• Increasing the relative integral dose
–
–
–
–
Conformal radiation therapy
Proton beam therapy
Brachytherapy + EBRT
Intensity modulated radiation therapy
• Decreasing the volume of tumour prior to RT
– Hormonal therapy
– chemo cytoreduction
• Radiobiologic optimization
– Altered fractionation
– Use of radiosensitisers
– Neutron beam therapy
Locally advanced prostate cancer
Hormone + Irradiation
Study
Median
FU
(yrs)
Stage
N
RX
Local
relapse
(%)
PFS (%)
OS (%)
RTOG 8307
7
B2,C
99
MEG
16
-
-
98
DES
21
-
-
477
LHRHa
16
53
75
468
None
29
20
71
226
LHRHa+ F
46
36
63
230
None
71
15
63
46
LHRHa
-
85
79
45
None
-
48
48
RTOG 85-31
RTOG 86-10
EORTC
4.5
4.5
3.8
T3,N1
T2C-T4
T3-T4,G3
RTOG 92-02
Locally advanced prostate cancer (PC; T2c-4) ,PSA <150 ng/mL.
N= 1554
goserelin and flutamide X 2 months
65-70Gy EBRT – Prostate, 44-50 Gy EBRT – Pelvic nodes
goserelin and flutamide X 2 months
No additional therapy
(short-term [ST]AD-RT)
24 months of goserelin
(LTAD-RT);
Hanks GE,J Clin Oncol. 2003 Nov 1;21(21):3972-8.
RTOG 92-02
•
The LTAD-RT arm showed significant improvement in all efficacy end
points except overall survival (OS; 80.0% v 78.5% at 5 years, P =.73).
•
Tumors with Gleason scores of 8 to 10, the LTAD-RT arm had
significantly better OS (81.0% v 70.7%, P =.044).
•
There was a small but significant increase in the frequency of late
radiation grades 3, 4, and 5 gastrointestinal toxicity ascribed to the
LTAD-RT arm (2.6% v 1.2% at 5 years, P =.037),
•
CONCLUSION: The RTOG 92-02 trial supports the addition of LT
adjuvant AD to STAD with RT for T2c-4 PC.
DFS
Overall survival for patients with Gleason scores 8 to 10
Primary hormone therapy
•
RP is often not done in patients with prostate cancer due to poor risk for surgery, patient's
wish, or physician's recommendation.
•
N =151 patients with T1b, T1c, T2a, T2b or T3a prostate cancer
•
Group I received leuprorelin acetate depot, 3.75 mg monthly
•
Group II received LH-RHa with chlormadinone acetate (100 mg/day).
•
At 12 weeks of treatment, 49% of the patients in both groups had a CR.
•
Of the patients showing a partial response (PR) after 12 weeks of treatment, 25% in Group I
and 52% in Group II improved to CR 1 year later (p<0.05).
•
Group II showed a longer progression-free survival (p <0.05).
•
PFS rates
•
–
T2b- 62% (Group I) and 91% (Group II)
–
T3- 43% (Group I) and 73% (Group II)
Early primary hormone therapy is a reasonable treatment option for localized or locally
advanced prostate cancer patients if radical prostatectomy was not scheduled.
Akaza H, Jpn J Clin Oncol. 2000 Mar;30(3):131-6.
•
Adjuvant flutamide treatment improves DFS but does not improve
median-term overall survival after radical prostatectomy for locally
advanced, lymph node-negative prostate cancer.
(Wirth MP, Eur Urol. 2004 Mar;45(3):267-70; )
Management of
hormone sensitive
metastatic prostate cancer
Goals of treatment
• Prolonging survival
• Preventing or delaying symptoms due to
disease progression
• Improving and maintaining QOL
• Reducing treatment related morbidity.
Treatment options
• Androgen Deprivation
– Bilateral orchiectomy
– LHRH analogues - Goserilin, Leoprolide etc.,
– Total androgen Blockade : e.g..,adding flutamide
• Experimental options
– Intermittent androgen suppression
• Treatment of Local Symptoms
– "Channel" TURP.
– Prostatic Urethral stenting
– External Beam Radiotherapy
Physiology of androgens
Orchidectomy
Questions!
• What are the standard initial treatment
options?
• Are antiandrogens as effective as other
castration therapies?
• Is combined androgen blockade better than
castration alone
• Is early androgen deprivation therapy better
than deferred ADT?
• Is intermittent ADT better than continuous
ADT?
What are the standard initial treatment
options?
•
Orchidectomy
•
LHRH analogues
•
Diethystilbesterol
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Simple & cost effective
Quick palliation
Compliance not a problem
Nonreversible
Carries significant psychological burden
Risk-Surgical complications
Side effects-Vasoactive symptoms, weight gain, mood lability, gynecomastia, fatigue, loss of libido,
cognitive changes, osteopenia, hypercholesterolemia
Costly
Risk of tumor flare
Potentially reversible
Convenient
No psychological burden
Side effects-Vasoactive symptoms, weight gain, mood lability, gynecomastia, fatigue, loss of libido,
cognitive changes, osteopenia, hypercholesterolemia
Convenient oral route
Risk of thrombosis & cardiovascular complications, edema, dyspnea, cramps
Compliance
No psychological burden
Single-Therapy Androgen Suppression in Men with Advanced
Prostate Cancer: A Systematic Review and Meta-Analysis
• 24 RCT involving 6600 patients, (1966 - 1998)
• Results
– LHRHa are equivalent to orchiectomy (10 trials, n=1908, HR1.262, 95% CI, 0.915-1.386).
– There was no difference in OS among the LHRH analogues
• Leuprolide (hazard ratio, 1.0994 [CI, 0.207 to 5.835])
• Buserelin (hazard ratio, 1.1315 [CI, 0.533 to 2.404])
• Goserelin (hazard ratio, 1.1172 [CI, 0.898 to 1.390]).
– Nonsteroidal antiandrogens are associated with lower OS( 8
trials, 2717 patients, HR 1.2158 [CI, 0.988 to 1.496]).
– Treatment withdrawals are less frequent with LHRHa (0% to
4%) than with nonsteroidal antiandrogens (4% to 10%).
Seidenfield et al Annals of Intern Med 2000, 132; 7: 566-577
• Conclusions:
– Survival after therapy with an LHRH agonist was equivalent to
that after orchiectomy.
– No evidence shows a difference in effectiveness among the LHRH
agonists.
– Survival rates may be somewhat lower if a nonsteroidal
antiandrogen is used as monotherapy.
Are antiandrogens as effective as other castration therapies?
• Antiandrogens
– Nonsteroidal (Flutamide,Bicalutamide, Nilutamide)
• Side effects-Gynecomastia, breast pain, hepatotoxicity
– Steroidal (Cyproterone acetate)
• Side effects-Hepatotoxicity, edema, weight gain
• Monotherapy with nonsteroidal antiandrogens has
equivalent survival to orchidectomy but with less
toxicity (Seidenfield et al. AIM, 2000)
• Steroidal aniandrogens have an inferior TTP as
compared to LHRHa (Thorpe et al, Eur Uro,1996)
Is combined androgen blockade better than castration alone?
Combined androgen
blockade consists
of an antiandrogen
drug plus
castration.
Is combined androgen blockade better than castration alone?
• N=1387 patients (Orch + Flutamide group-700,Orch + Placebo
group-687)
• Patients receiving flutamide had greater rates of diarrhea and
anemia .
• There was no significant difference between the two groups in
overall survival (P=0.14).
• HR for flutamide as compared with placebo was 0.91 (90 % CI0.81-1.01).
• Flutamide was not associated with enhanced benefit in patients
with minimal disease.
• Conclusions The addition of flutamide to bilateral orchiectomy
does not result in a clinically meaningful improvement in survival
among patients with metastatic prostate cancer.
Eisenberger et al, NEJM,1998,339;1036-1042
Metaanalysis of CAB-1
•
20 trials (6,320 patients).
•
The pooled OR for overall survival was
– 1.03 (95% CI:0.85 to 1.25) @ 1year
– 1.16 (95% CI:1.00 to 1.33), @ 2 years
– 1.29 (95% CI:1.11 to 1.50) @ 5 years
•
OS was only significant at 5 years.
•
PFS was improved only at 1 year follow-up (OR=1.38)
•
Cancer-free survival was improved only at 5 years (OR=1.22).
•
Adverse events occurred more frequently with CAB and resulted in
drug withdrawal in 10%.
•
Quality of life was better with orchiectomy alone
Conclusion
•
MAB produces a modest overall and cancer-specific survival at 5 years
but is associated with increased adverse events and reduced quality of
life.
Schmitt B et al. Cochrane Reviews 1999, Issue 2.
Metaanalysis of CAB-2
• Metaanalysis of individual patient data
• 27 RCT, n=8275 men (Metastatic-88%, Locally advanced-12%
• Results
– 5932 (72%) men died; 80% deaths attributed to prostate cancer.
– 5-year survival was 25·4% with MAB vs 23·6% with AS alone (2p=0·11).
– The results for cyproterone appeared slightly unfavourable to MAB
(5-year survival 15·4% MAB vs 18·1% AS alone; 2p=0·04)
– The results for nilutamide and flutamide appeared slightly favourable
(5-year survival 27·6% MAB vs 24·7% AS alone; 2p=0·005).
– Non-prostate-cancer deaths accounted for some of the apparently
adverse effects of cyproterone acetate.
• Conclusion
– In advanced prostate cancer, addition of an antiandrogen to AS
improved the 5-year survival by about 2% or 3% (range 0-5%. )
PCTC meta-analysis .Lancet 2000, 355; 9214:1491-1498
Conclusions-CAB
• The findings range from no benefit (17 studies) to an estimated
3.7-7 months’ survival improvement(3 studies)
• In metaanalysis, CAB offers a stattistically significant but
clinically questionable improvement in survival over orchidectomy
or LHRHa monotherapy
• Benefit of CAB is limited to patients taking only NSAAs
• Benefit of CAB is seen only after 5 years
• GI (diarrhea, pain) & ophthalmologic side effects are more with
CAB
• CAB results in 1 million $ per quality adjusted life year over
orchidectomy alone
Early versus Late ADT
• 4 trials (n=2,167)
– All trials were conducted prior to use of PSA testing & were
heterogenous
– All studies found PFS was consistently better in the early
intervention group at all time points.
Overall Survival (%)
1 yr
2 yr
5 yr
10 yr
Early ADT
88
73
44
18
Deferred
ADT
86
71
37
12
1.16
95% CI: 0.90 to 1.49
1.08
95% CI: 0.89 to 1.33
1.19
95% CI: 0.95 to 1.50
1.50
95% CI: 1.04 to 2.16
OR
Wilt T, et al Cochrane Reviews 2001, Issue 4.
OS
PFS
Early versus Late ADT
•The pooled estimate for the difference in OS survival favored early
ADT but was significant only at 10 yrs
•The pooled estimate of prostate cancer specific survival at 2, 5, and
10 years favored early therapy but were not statistically different.
•The risk differences at 2, 5, and 10 years were 2.7%, 5.8%, and
4.6%.
Wilt T, et al Cochrane Reviews 2001, Issue 4.
Timing of ADT
Conclusions
• The evidence from RCTs is limited by the
–
–
–
–
–
–
variability in study design,
stage of cancer and
subjects enrolled,
interventions utilized,
definitions and reporting of outcomes and
Lack of PSA testing for diagnosis & monitoring
• Additional studies are required to evaluate more definitively the
efficacy and adverse effects of early ADT
• In particular trials should evaluate the impact of early ADT in
patients with rising PSA syndrome
Timing of ADT
Conclusions
• Early ADT offers a statistically significant benefit in PFS & OS
• Early ADT reduces disease progression and complications due to
progression.
• There was no statistically significant difference in prostate cancer
specific survival
• Early ADT leads to higher costs
• Treatment is most cost effective when started after the onset of
symptoms
• Complications due to disease progression are more frequent in the
deferred treatment group.
• Adverse events due to treatment are more frequent in the early
treatment group.
Is intermittent ADT better than continuous ADT?
•
Rationale
– Prolonged ADT may cause androgen independence
– Side effects are lesser with intermittent ADT
•
No prospective randomized trials
•
No guidelines for starting & stopping therapy
•
No data available on testosterone levels, QOL, BMD & sexual function
•
Two phase III studies are underway
Management
of
Hormone Refractory
Prostate Cancer
Hormone refractory prostate carcinoma
• Definition:
Disease progression despite castrate serum levels of testosterone
• Progression’ is defined by:
– Increase in size of measurable lesions
– Appearance of new measurable lesions
–
Increase in PSA >50% on at least 2 consecutive measurements
– Increase in pain associated with new bony lesions
• Duration of response
– Limited or no metastases-5 years
– Metastatic disease-2 years
• Median survival approximately 1 year
Considerations in the management of HRPC
•
Is the patients functionally castrated?
•
What are the previous therapies?
•
What was the response to previous therapy?
•
What was the duration of response
•
What is the current pace of the disease?
•
Is the disease localized or metastatic at recurrence?
•
Is the patient symptomatic?
•
What are the sites & number of metastasis?
•
Is there a risk of Pathologic # or cord compression?
•
What are the comorbidities?
•
Is the organ function compromised?
Management Options in HRPC
•
•
•
•
•
•
•
•
•
•
•
–
–
–
–
–
–
Observation
Withdrawl therapies
Second line hormonal agents
Estrogenic compounds-DES, Fosfetrol
Antiandrogens-Bicalutamide, Flutamide, Nilutamide
Adrenal suppressants-Ketoconazole, Aminoglutethimide
Glucocorticoids-Prednisone, Dexamethasone, Hydrocortisone
Chemotherapy
For skeletal metastases
Bisphosphonates
External beam radiotherapy
Bone seeking radiopharmaceuticals-Sumarium153, Strontium89
Adjunctive therapies
Pain management
Radiofrequency ablation
Cryotherapy
Investigational therapies
Antiandrogen withdrawl
• Preferred for patients who are using antiandrogens or CAB
•
•
•
Withdrawl responses can be seen with
–
Nonsteroidal antiandrogens
–
Diethylstilbesterol
–
Megestrol acetate
–
Estramustine
–
Ketoconazole
Response rates ~20%
–
Decline in PSA level
–
Occassional radiographic responses
Expected timing of response
–
Flutamide-4 weeks (Half life of 6 hours)
–
Bicalutamide-8 weeks (Half life of 6 days)
•
Response duration 4-6 months
•
Continuation of LHRHa indefinitely despite relapse may be beneficial
Second line hormonal agents
•
For patients who have received monotherapy (LHRHa/orchidectomy), addition of
an antiandrogen is useful.
•
Patients may respond differentially to different antiandrogens
•
No major symtomatic relief
•
More beneficial in
•
–
asymptomatic patients
–
biochemical failures
Effects are short lived
–
•
median duration of response- 2-6 months
Combining second line agents with AA does not confer any benefit & therefore
should be used sequentially
Role of chemotherapy
Role of chemotherapy in HRPC
•
Until 1990, chemotherapy was considered to have no role in the
management of HRPC
•
Active agents
– Taxanes-Docetaxel, Paclitaxel
– Mitoxantone
– Estramustine
– Adriamycin
– Vinorelbine
– Carboplatin
•
Mitoxantrone is FDA approved for use in HRPC for palliation. It does
not confer a survival benefit
Chemotherapy regimens in HRPC
Chemotherapy
PSA
response (%)
Measurable
Response (%)
33
-
Estramustine + Vinblastine
31-54
14-43
Estramustine + Taxane
62-65
43-57
Estramustine + etoposide +/- platinum
52
50-61
Estramustine + etoposide + paclitaxel
53
40
Doxorubicin + ketoconazle
55
58
Doxorubicin + ketoconazle/ vinblastine +
estramustine
67
75
Mitoxantrone+ Steroids
Role of Docetaxel
Advanced refractory prostate cancer
Docetaxel-60 mg/m2- Day 2
Estramustine - 280 mg TDS-Day 1-5
Dexamethasone-60 mg Day2
Mitoxantrone-12 mg/m2
Prednisolone-5 mg BD
n=338
n=336
Median OS-17.5 mo
Median OS-15.6 mo
P=0.02
Median TTP-6.3 mo
Median TTP-3.2 mo
P<0.001
PSA response-50%
OTR-17%
PSA response-27%
OTR-11%
P<0.001
P=0.30
Grade 3 or 4 neutropenic fevers, nausea and vomiting , and cardiovascular events were more
common among patients receiving docetaxel and estramustine.
Petrylak et al NEJM, 351:15:1513-1520
Role of Docetaxel-2
Advanced refractory prostate cancer
Docetaxel-75 mg/m2- Day 1
Dexamethasone-24 mg Day 1
Prednisolone-5 mg BD
Docetaxel-30 mg/m2/wk X 5 wk
Dexamethasone-24 mg Day 1
Prednisolone-5 mg BD
Mitoxantrone-12 mg/m2
Prednisolone-5 mg BD
n=332
n=330
n=335
Median OS-18.9 mo
Median OS-17.4 mo
Median OS-16.5 mo
P<0.001
Pain relief-35%
Pain relief-31%
Pain relief-22%
P=0.01
PSA response-45%
PSA response-48%
PSA response-32%
P=0.005
Tannock et al NEJM, 351:15:1502-1513
Tannock et al NEJM, 351:15:1502-1513
Tannock et al NEJM, 351:15:1502-1513
Conclusions
• Goal of chemotherapy for hormone
refractory prostate cancer mainly to
relieve symptoms
• Modest survival advantages have now
been shown with some regiments
Bisphosphonates
• Incidence of bone metastases: 65%–75%
• Classification: osteolytic, osteoblastic, or
combination/mixed
• Etiology: activation of osteoclasts and osteoblasts by
soluble mediators released by prostate tumor cells
metastasized to bone
• Treatment with a LHRHa decreases BMD and
increases the risk of fracture in men with prostate
cancer.
• Pamidronate has been shown to prevent bone loss in
this group of patients.
Smith et al NEJM, 2001,345:13:948-955
Rationale for using bisphosphonates
• Preferentially bind to bone surfaces undergoing active
remodeling
• Inhibit osteoclast maturation and suppress osteoclast function
• Inhibit osteoclast recruitment to site of bone resorption
• Reduce bone-resorbing cytokine production
• Inhibit tumor-cell invasion and adhesion to bone matrix
• Induce apoptosis in tumor-cell lines
• May inhibit tumor-cell secretion of growth factors that
stimulate osteoblasts
• Inhibit number and activity of osteoblasts
Role of bisphosphonates
• Randomized, double-blind placebo-controlled trial
• Randomization to
Proportion of patients
– Intravenous Zolendronic acid 4 mg (n=214)
– Intravenous Zolendronic acid 8 mg (n=221)
– Placebo (n=208)
0.8
0.7
0.6
P=.021
ZOMETA® (zoledronic acid) 4 mg
Placebo
0.5
0.4
0.3
0.2
0.1
0
All patients
Saad et al, JNCI,2002;94:1458-1468
10
0
Median Time:
ZOMETA® (zoledronic acid) 4 mg
= N.R.
Placebo = 321 days
90
80
Percent of patients
without event
70
60
50
40
30
20
10
0
P=.011
0
450
50
500
100
550
150
200
250
300
350
400
Time after start of therapy (days)
N.R. = not reached
Time to first skeletal-related event (SRE)
Saad et al, JNCI,2002;94:1458-1468
2.8
ZOMETA® (zoledronic acid) 4 mg
Placebo
Mean rate
2.4
2
P=.006
1.6
1.2
0.8
0.4
0
All patients
Skeletal morbidity rate
Percent of patients
without event
100
90
80
70
25% Quartile Time:
ZOMETA® (zoledronic acid) 4 mg =
N.R.
Placebo = 321 days
60
50
40
P=.011
30
20 0
10
0
50
100
150
200
250
300
350
400
450
500
550
Time after start of therapy (days)
N.R. = not reached
Saad et al, JNCI,2002;94:1458-1468
ZOMETA® (zoledronic acid) 4 mg
Placebo
1
Mean change from baseline
0.9
P=.03
0.8
0.7
0.6
0.5
P=.003
0.4
0.3
0.2
0.1
0
3
6
9
12
15
Time on study (months)
Change in composite pain score
Saad et al, JNCI,2002;94:1458-1468
Palliative measures
•
External beam RT (Local/Hemibody irradiation)
– Painful bony metastases,
– Spinal cord/nerve root compression
•
Radio isotopes (Strontium-89 and Sumarium-153, Rhenium-188)
–  -emitting isotopes which can improve bone pain
– Administered as a single dose
– Response rate –35-89%
– Duration of response-3-12 months
– Flare can occur in upto 23% of patients
– More effective in combination with EBRT(Porter etal , IJROBP,1993)
•
Anticholinergics
•
Limited TURP for obstruction
•
Radiofrequency ablation
•
Cryosurgery
•
Chemoembolization
Newer agents
•
•
•
•
•
Satraplatin
PC-SPECS
Panzem (2-methoxyestradiol)
Calcitriol
Tyrosine kinase inhibitors
– Imatinib,
– Gefitinib
•
•
•
Thalidomide
Bortezomib
VEGF inhibition– Bevacizumab,
– SU-5416
•
•
Flavopiridol
GM-CSF
• Exisulind
• Trastuzumab
• Epothilone B analog
– BMS-247550
• Somatostatin Analogue
– sms-D70
• Rhenium-188
• Endothelin-A Receptor Blockade
– Atrasentan
• Antisense Oligonucleotides
– ISIS 3521
– ISIS 5132
• Gene therapy