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Primary Androgen Deprivation for
Prostate Cancer
(February 2007)
Older, yes; "old" - no
way! As demographics relentlessly shove more men into the upper age
brackets, their prevailing claim is a humble origin in Lake Wobegon, where
"everyone is above average". Unfortunately, however, mortality statistics
have a way of gaining the upper hand, and therein lies the clinicians'
dilemma in guiding e.g. a newly diagnosed 75 year-old through a balanced
discussion of management options for his prostate cancer. Suppose he is
active with no other health issues, Stage T1c, PSA 22 ng/mL, and Gleason
score 8. Actuarial life tables soberingly indicate a median longevity for
this age group of 9.8 years. Although generally useful, the Kattan
nomogram does not take age and co-morbidities into account in its
projections. What does the literature report about the outcome of primary
androgen deprivation therapy (PADT), as opposed to ADT combined with
radiation therapy or prostatectomy for high-risk localized cancer in this
older age group?
The most informative data
comes from Japan, where almost half of patients with localized prostate
cancer are treated with androgen deprivation, regardless of disease stage.
i.e. 57% of all patients, and 46% of those with T1c to T3 disease. CaPSURE
data likewise shows that primary androgen deprivation for men at high-risk
for recurrence is increasingly being chosen as an option - increased to
48.2% in 2001 as opposed to 32% in 1989 (Sweeney, C. "The Case for
Systemic Therapy Alone for Prostate Cancer" J Urol. 2006, Dec 176 ,
6 Pt 2). Three area are covered below: 1) PADT versus surgery plus ADT;
2)combined androgen blockade (CAB) versus LHRH monotherapy; and
3)classification of response to PADT according to subsets of patient
characteristics.
1. "Efficacy of primary
hormone therapy for localized or locally advanced prostate cancer: results
of a 10 year follow-up" was reported by Akaza et al. in BJU Int.
98(3):2006 Sep. Their trial evaluated whether prostatectomy added benefit
to ADT as monotherapy. They studied two groups of men with T1b, T1c or
T2-3. Group 1 involved 176 men (mean age 67.2 years) who underwent
prostatectomy followed by an LHRH agonist; in Group 2, 151 men (mean age
75.5 years) had no surgery but only an LHRH agonist or combined
androgen blockade. Results at a median follow-up of 10.4 years: for Group
1 the 10-year overall survival (OS) was 73% and the 10-year
cancer-specific survival (CSS) was 86%, versus OS of 41% and CSS of 78% in
Group 2. Their conclusion: "With primary hormone therapy or
prostatectomy, the men had a life-expectancy similar to that of the normal
[age-matched] population," and "There was no difference between studies in
cause-specific survival."
2. "Global update on
defining and treating high-risk localized prostate cancer with leuprorelin:
a Japanese perspective - the effect of primary androgen deprivation
therapy on stage C prostate cancer", ( Akaza BJU Int 2007; 99,
Supp. 1, 10-12) reports a significant superiority in progression-free
survival for combined androgen blockade (CAB) in 78 men, compared with
monthly Lupron alone for 73 men. The median follow-up was 10 years.
Hormone therapy was administered for two years with continuation at the
physicians' discretion. Mean patient age was ~75 years. In the Lupron arm
43% had T3 disease; and in the CAB arm, 47%. Patients were stratified by
PSA, Gleason score, and T Stage. The graphic presentation shows
progression-free survival for CAB at six years of 60%, and 30% for Lupron
monotherapy (p=0.05). There was no difference in overall survival among
any of the stratified risk groups. In this study the antiandrogen was
chlormadinone.
Akaza's article included the second interim report
of an ongoing study of men with advanced stage C and D disease that found
that CAB ( LHRH agonist plus bicalutamide 80 mg/day; 102 men ) produced a
significantly longer time to disease progression (p=<0.001) compared to
LHRH monotherapy (101 men) in the subset of stage C patients receiving
PADT. The final results are pending.
3. The most informative
report for clinicians confronting this management decision for older men
is "Global update on defining and treating high-risk localized prostate
cancer with leuprorelin: an Asian perspective," Akaza et al. BJU Int
2007; 99, Supp. 1, 6-9. This study of 628 men suggests a practical
treatment algorithm which incorporates stratification into modified
D'Amico risk groups and uses the PSA nadir after 6 months of PADT as a
decision point at which to continue ADT or add irradiation. Once again CAB
proved significantly (P=0.037) more effective in extending CSS then LHRH
agonist monotherapy.
"The results showed that, even if a patient is classified
as 'high-risk', a good prognosis could normally be predicted based on
certain variables: if his initial prostate-specific antigen (PSA) level
was <20 ng/mL, his Gleason score was <6, and his PSA
decreased to <0.2 ng/mL within 6 months of HT." High-risk was
defined as PSA > 20 ng/mL, a Gleason score of >8 or
stage >T3, and 376 men in their study met one or more of these
criteria. Of the high-risk patients, 60% had relapsed before 10 years.
"However, 40% did not relapse by 10 years, so the focus of our studies
should be on how we can identify this subgroup and treat them
accordingly."
Their suggested management algorithm: Initiate therapy with
six months of CAB. Those men who show a PSA nadir of <0.2 ng/mL and
achieve this level within 6 months, i.e. "good responders", may
continue on CAB (or intermittent CAB), but if these criteria are not met,
then combined therapy with CAB and some type of radiation therapy can be
considered.
Bottom Line:
The efficacy of primary therapy with combined androgen blockade for older
men with localized or locally advanced prostate cancer has been
sufficiently validated so that it may be included in the discussion of
management options.
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