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Neoadjuvant chemotherapy for "high risk" prostate cancer - ready for prime
time?
It is routine these days at urology tumor boards for clinicians to ponder
whether neoadjuvant therapy would be of benefit to patients presenting
with "high risk for recurrence" prostate cancer. Neoadjuvant treatment
with hormonal, chemo-hormonal, or chemotherapy, preceding primary therapy
(surgery or irradiation) is under widespread active study. And rightly so,
since the prospects for sustained freedom from biochemical relapse and
ultimate survival are so significantly diminished in this group. Based on
an analysis of outcome after radical prostatectomy or radiation therapy,
researchers have arrived at a rough consensus that associates "high risk"
with a clinical Stage of T2b ('92) or greater, and/or Gleason 8 - 10,
and/or PSA usually >l5 or >20 ng/ml. The need for improvement is evident
by placing a clinical example with the minimum parameters of this
definition into the Kattan outcome nomogram [discussed in PCa Commentary
of October 2002]. The result: likelihood of organ confined disease, 7%,
and capsular penetration >40%; 5 year likelihood of freedom from PSA
recurrence from surgery 30%, or from external beam irradiation (78 Gy)
40%. An excellent recent article that presents a balanced view of the
current status of this issue was presented by Hussain in UROLOGY, April
2003: "Neoadjuvant Docetaxel and Estramustine Chemotherapy in
High-Risk/Locally Advanced Prostate Cancer."
The initial efforts to improve treatment outcome initially involved the
neoadjuvant use of androgen suppression, usually with an LHRH agonist
preceding surgery or preceding and concomitant with irradiation. Study
strategies have been segregated based on duration of treatment, i.e. 3
months or less versus longer - variously up to 12 months. A substantial
consensus of opinion finds that treatment of 3 months or less offers no
improvement in outcome over primary therapy alone at the five year
benchmark. Meyer (UROLOGY 2001 Aug) reports the Laval University, Quebec,
experience in which 756 men were treated between 1991-1998 and PSA failure
was set at >.3 ng/ml. Of these, 240 men received androgen suppression for
3 months or less, 129 men for >3 months, and 516 men had RP alone. The <3
months group gained no benefit. In their study the "longer" treatment
group enjoyed a longer disease-free survival (hazard ratio .6) at the
median follow-up of 4 years. However, this conclusion was challenged by
Dr. Martin Gleeve at the April 2003 AUA meeting reporting the British
Columbia study of 502 men who received Lupron and flutamide for either 3
or 8 months prior to RP. At 4 years post surgery the PSA recurrence was
similar: 23.6% (8 months) and 25.4% (3 months). The study had no control
arm of RP only.
The logical next step has been to evaluate chemotherapy in the neoadjuvant
setting. This endeavor is in its infancy. Based on the tentative and
hopeful evidence that chemotherapy may have usefulness in the treatment of
metastatic PC [see PCa Commentary, February 2003] docetaxel, mitoxanthrone,
estramustine (and others) in various combinations have been use
neoadjuvantly, sometimes combined with hormone suppression (again for
various durations). The rationale underlying the chemo/hormonal therapy is
that at the outset PC is heterogeneous as to cellular sensitivity to
androgen deprivation and that chemotherapy might address the androgen
insensitive component. It's important for clinicians to realize that when
the chemotherapy drug estramustine ("EMCYT") is used, the treatment
becomes "chemo-hormonal", since the Hussain article documents that
estramustine even at a seemingly low dose of 280 mg TID X 3 days q 3 weeks
lowers serum testosterone to castrate levels (<50 ng/dL) by the end of the
first three week cycle. And since so many of the current regimens include
this drug, an unresolved issue is what contribution chemotherapy may add
to the androgen diminishing effect of estramustine. Two trials have used
single agent neoadjuvant docetaxel/surgery versus surgery alone and, as
also seen in the neoadjuvant hormonal trials, the incidence of positive
tumor margins at RP was reduced. The ultimate utility of this reduction
awaits further follow-up. In the Hussain study 70% of RP specimens showed
negative margins, but no specimen was free of cancer. For comparison,
neoadjuvant studies in breast cancer have shown that a survival benefit is
achieved only when a complete pathologic remission is effected. At this
stage of investigation of neoadjuvant therapy for PC the available early
data only relates to the extent of PSA decline and a comparative
improvement in negative surgical margins.
A word of caution against premature assumptions of success for neoadjuvant
therapy arises from consideration of the experience of neoadjuvant therapy
in prostate's sister endocrine sensitive disease, breast cancer. Post-
operative adjuvant chemotherapy in breast cancer has been studied since
1965, and neoadjuvant treatment more recently. It's well recognized that
chemotherapy in this disease has a success record that far exceeds that
for chemotherapy's fledgling role in PC. Postoperative chemotherapy in
breast cancer delays disease recurrence by three to four years and confers
a small long-term survival benefit. There is no similar body of data for
post-operative chemotherapy in PC, although some studies are in progress.
Encouraged by success in the use of post-operative adjuvant chemotherapy
for breast cancer, study groups moved chemotherapy into the preoperative (neoadjuvant)
position and by 2001 were able to report a large experience. The outcome:
no overall survival advantage resulted from neoadjuvant chemotherapy
compared to the standard post-operative timing. This was the overall
outcome despite extensive shrinkage of tumors and a modest numbers of
complete pathologic responses. Neoadjuvant treatment in PC, however, is
being moved to the front position without any convincing positive data
from post-operative adjuvant trials.
The motivation to employ neoadjuvant therapy for PC arises from a very
evident need and a hope based on a hypothesis. No assurance of success can
be given to any individual patient to offset the potential toxicities he
may experience from treatment. Currently, neoadjuvant (hormonal and/or
chemotherapy) treatment can be best justified by incorporation into a well
designed clinical trial. Since many or most "high risk" patients are
appropriate candidates for irradiation, physicians should consider
entering them into clinical trials such as "Phase III Randomized Study of
Neoadjuvant Total Androgen Suppression and Radiotherapy in Patients With
Intermediate-Risk Adenocarcinoma of the Prostate" (RTOG 9910), or "Phase
III Randomized Study of Androgen Suppression and Radiotherapy With or
Without Subsequent Paclitaxel, Estramustine, and Etoposide in Patients
With Localized High-Risk Prostate Cancer" (RTOG-9902) - or any other
appropriately designed trial.
Bottom Line: The benefit of neoadjuvant therapy for PC will need to
be clearly established in clinical trials before this type of treatment is
accepted as a standard option.
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