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Adjuvant
Hormone Intervention: Is The Strategy Shifting?
(November 2006)
Medical oncologists who
have been active in the management of both prostate
and breast cancer recognize that the basics of the molecular biology of
breast cancer are paralleled in prostate cancer, but for their
subsequent translation into treatment regimens in the management of
prostate cancer there is a lag period of possibly 15 or more years.
Adjuvant chemotherapy for node-positive breast cancer was developed in
the mid 1960s, and adjuvant taxoxifen for estrogen receptor positive
breast cancer emerged in the 1970s.
After Craig Jorden's
discovery of tamoxifen, now termed a selective estrogen receptor
modifier (SERM), and after appropriate studies, intervention with
surgical oophorectomy gave way to tamoxifen. Although not without side
effects, the ratio of therapeutic benefit to side effects for tamoxifen
is very favorable and this has made its use acceptable in the
earliest asymptomatic stages of breast cancer.
In prostate cancer
management GnRH agonists, e.g. Lupron, have conventionally filled the
role of an early adjuvant hormonal intervention, especially in patients
at high-risk for recurrence. But the strategy of androgen depletion is
increasingly recognized to carry unwelcome toxic baggage - hot flashes,
loss of muscle mass and weakness, weight gain, fatigue, osteoporosis and
increased fracture risk, loss of libido and erectile function, lipid
abnormalities, mood lability, memory degradation, and now, disorders in
glucose metabolism. With the development of inhibitors of androgen
receptor function, e.g. bicalutamide, and agents that decrease the
delivery of testosterone to the prostate, e.g. 5-alpha reductase
inhibitors - neither of which lower serum testosterone levels
- prostate cancer management has been provided with effective
alternative agents for adjuvant hormonal treatment. As a consequence of
their relatively low side effect profiles, these drugs can be deployed
with greater patient acceptance at a much earlier disease stage
compared to standard GnRH agonists. It is now recognized that even in
"androgen independent" prostate cancer, signaling through the androgen
receptor (AR) continues to play an important role, and bicalutamide,
which functions as a co-repressor of AR function, can interfere with
alternate pathways of activation commandeering the AR from a variety of
growth factors, such as Her 2/neu and the epidermal growth factor.
So where do these
considerations lead in the evolution of adjuvant hormonal interventions
in early prostate cancer with agents less toxic than GnRH agonists,
especially for men at high-risk for recurrence? D'Amico's low- and
intermediate-risk groups, based on patterns of PSA, Gleason score, and
tumor stage, are in fact heterogeneous in composition, each
incorporating a spectrum of risk. There are men in those "favorable"
groups who already have occult regional or distant metastases, and
others who possess an inherent high-risk to spread at a very early
stage. Some examples: about 10% of "low-risk" men at extended
lymphadenectomies show lymph node spread; even some "low-risk" cancers
lack the metastases suppressing adhesion molecule, E-cadherin and other
tumor suppressors; and emerging proteomic, epigenetic, and gene
expression analyses have the capacity to identify men harboring
high-risk features, who on the basis of conventionally classification
would be placed in a lower risk group. If a treatment with a more
acceptable side-effect profile than (say) Lupron can be developed and
found effective, these men would also benefit early adjuvant hormonal
intervention.
Abstract 4573 presented
at the 2006 ASCO Annual Meeting by Picus, Small, Vogelzang et al, "Long
term efficacy of peripheral androgen blockade on prostate cancer : CALGB
9782", reports the results of a "kinder and gentler" regimen of hormonal
intervention: finasteride 5 mg QD/flutamide 250 mg TID. Ninety eight men
were evaluable, each experiencing a rising of PSA, above 1 ng/mL, with
no detectable evidence of recurrent disease 1 to 10 years after primary
treatment. Median follow-up was 59 months. "A >80 PSA decline was seen
in 91/94(97%) of the patients", and two others declined 77% and 73%.
These nadirs were achieved at a median of 3.2 months. The authors
concluded that this regimen "showed excellent activity and produced
durable PSA responses." "The median duration of progression-free and
overall survival as not been reached, and is likely to be longer than
five years." Quality of life data will be reported later. Importantly,
of the 22 men who progressed, 15 responded to further hormonal
manipulation,(68%).
The CALGB study
received favorable comment from Judd Moul, MD, (Fall2006/THE ONCOLOGY
REPORT) who indicated that this regimen "has the advantage of not being
associated with hot flashes, weight gain, and loss of muscle mass and is
less likely than traditional hormone therapy to affect potency and
libido". Furthermore, in his experience "the known side effects of
gynecomastia and nipple tenderness can be lessened with low-dose breast
irradiation or tamoxifen".
The CALGB study was
begun in 1998 and, were it to be currently run, it is likely that
flutamide would be replaced by 50 mg of bicalutamide, a drug producing
less diarrhea and affording the convenience of once daily
administration. Wm. Oh, MD, prostate expert at the Dana-Farber Cancer
Institute, was unaware of any current protocols testing bicaultamide 50
mg/qd and finasteride 5 mg/qd in the adjuvant setting (personal
communication).
However, Dr. Oh was the
principle investigator for a report, "Finasteride [5 mg/qd] and
bicalutamide [150 mg/qd] as primary hormonal therapy in patients with
advanced adenocarcinoma of the prostate", Ann Oncol, June 2004. This
study established two important findings: 1) Finasteride added to the
effectiveness of bicalutamide. In the study the drugs were used
sequentially with bicalutamide first. "At the first nadir, median
decrease in PSA from baseline was 96.5%" (median PSA, 0.75 ng/mL; median
time to nadir, 3.7 weeks). After the first nadir, finasteride was added,
and the median PSA showed a further lowering to 0.35 ng/mL, a 98.5%
decrease from baseline. 2) Twelve of 14 (86%) men who subsequently
progressed on combined therapy "remained responsive to LH-RH
agonists" - a finding roughly similar to the CALGB results. Most
men in the Oh study had advanced disease, and the median duration of
response was 21.3 months, comparable, in the authors' opinions, to the
18-24 months median duration of response seen with LH-RH agonists in
study populations with similar characteristics.
Bottom Line:
Early adjuvant hormonal therapy with LH-RH agonists are associated with
a delay in disease progression and some prolongation of survival in
high-risk prostate cancer patients. However, these testosterone lowering
drugs subject men to the considerable toxicities of extended periods
of androgen deprivation. An alternative, as reported by Pinus,
suggests that adjuvant therapy with the androgen blocker bicalutamide
combined with finasteride (followed upon failure with an LH-RH agonist)
can achieve similar results with far fewer side effects. If randomized
studies demonstrate equal effectiveness for a regimen of peripheral
androgen blockade, then this therapy could also be acceptably applied to
men, who might conventionally be considered at lower risk, but who, in
reality, are at high-risk for recurrence as revealed by emerging
sophisticated genetic and molecular profiling.
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