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Chemotherapy For Hormone Refractory Prostate
Cancer: The Context and the New Content (August 2004)
A familiarity with
the natural history of hormone refractory prostate cancer (HRPC) gives
perspective for placing the results of the recently reported
chemotherapy trials into their full context. The classic contribution
that describes this “context” was the analysis by Drs. Pound, Partin,
Eisenberger and Walsh in JAMA, 1999, Vol 281: “Natural history of
progression after PSA elevation following radical prostatectomy”. In a
trial that could probably never be repeated, 1997 men who had a PSA
recurrence of > 0.2 ng/mL were followed without therapy
until the appearance of metastatic disease which developed at a
median of about 8 years. Factors that adversely hastened the time to
metatases were Gleason score > 8, PSA recurrence earlier than two
years post surgery, and PSA-DT of <10 months. Androgen deprivation was
effected at this point, and the median time to death was about 5 years.
(See Figs 1,2.) This interval was progressively longer if the metastases
occurred at 1-3, 4-7, or > 8 years after surgery.
A second informative
“natural history” analysis came from Oefelein et
al, J Urol April 2004: “Survival of patients with hormone refractory
prostate cancer in the prostate specific antigen era”. The study
identified 254 men with HRPC enrolled in phase II and III clinical
trials and determined the time from
PSA elevation of > .3 ng/mL to death. The median survival of the men
who entered this period of HRPC with a positive bone scan was 40
months, and for those without bone scan evidence of metastases, 68
months. For all men in the study the median survival was about 4 1/2
years. Oefelein’s conclusion was that the “historically reported
survival of 12 to 18 months after HRPC develops requires clarification
and revision”. He observed that trials conventionally calculate survival
from the date of enrollment, and that “this convention truncates the
duration of survival because the patients enrolled are frequently far
along in the hormone refractory disease course,” as was the case in the
two recent trials that will be discussed next.
Figure 2
In the October 7, 2004
issue of the NEJM two major phase III chemotherapy trials were reported
for men with HRPC. The Tax-327 trial compared two regimens of docetaxel/prednisone
to mitoxanthrone/prednisone and reported a median survival for the
weekly docetaxel regimen at 17.4 months, for q 3 week docetaxel - 18.9
months, and for mitoxanthrone - 16.5 months (docetaxel arms vs.
mitoxanthrone significant at P=0.05). In the SWOG 99-16 trial the
combination of docetaxel/estramustine (D/E) showed a median survival of
17.5 months compared to the mitoxanthrone/prednisone (M/P) arm, 15.6
months (P=0.02). Supporting Oefelein’s observation, however, these
trials enrolled patients that were “far along in the hormone refractory
disease course”. The median PSA values at entry for the Tax-327 study
were 108,114,123 ng/mL and 90% of men had a positive bone scan. For the
SWOG trial the median entry
PSA was 87 ng/mL and ~ 85% of men were bone scan
positive.
The percent of trialists
who achieve a PSA reduction of greater than 50% is a common parameter of
comparison between studies. In the Tax trial a better than 50% PSA
reduction was seen in 45%-48% of men compared to the mitoxanthrone arm,
32%. In the SWOG trial the percentage showing more than 50%
PSA reduction for docetaxel/estramustine was 50% vs. 27% for
the mitoxanthrone arm. However, Dr. Eisenberger and others have pointed
out that comparisons based on
PSA reductions can be misleading. He has argued that the
important comparative observation regarding trial outcomes is the median
time to disease progression (TTP), which, interestingly, is about 5 to 6 months in all of
the recent trials employing, as they did, a variety of agents. This
similarity in TTP
suggests that each of the regimens interrupted the ultimate progression of
the disease to the same extent. A treatment regimen that exacts greater
toxicity without producing improvement in “time to disease progression”
may not be conferring a benefit commenserate with toxicity despite showing
a superior percent of PSA reduction or a longer median survival, or even a
modest increase in overall survival in comparison with a regimen with an
equivalent TTP and less toxicity. This consideration calls into question
the use of estramustine, since its inclusion in a regimen adds
significantly to toxicity.
The statistically
unsophisticated person reading the media announcements reporting that
chemotherapy now confers a “survival benefit” might easily be excused for
thinking that all persons receiving the “better” treatment would enjoy a
comparatively longer life, (i.e., the SWOG trial showed a two month
prolongation in median survival). In fact, the maximal comparative
survival benefit of two months is only “realized” by a man dying at the
median point of the curve compared to a man dying simultaneously at a
parallel point on the curve of the alternative trial arm. With increasing
time beyond the mid-point of the curves the comparative survival benefit
progressively decreases until at about 4 years there is no survival
benefit between the treatment arms and all the men had died. Figure 3
below shows data from SWOG 99-16 that illustrates this point.
Figure 4 displays
“progression-free survival” for SWOG 99-16, in an analysis often described
as a “time to progression” curve. A typical “duration of PSA
response” to chemotherapy may be 3 to 4 months, and the “time to
disease progression” - in this study a median time of 6.3 months
for the D/E arm from the start of therapy to the point of PSA progression
- is the sum of the response duration (if any) and the additional time
required to return to the pre-response PSA value. There is no evidence
that a tumor’s growth rate changes after a temporarily successful
chemotherapeutic intervention. Since all trialists ultimately showed
progression by about 36 months, it could be said that the D/E regimen
effected a comparatively longer “postponement of progression” than M/P.
The “payment” for these
benefits - the postponement of progression and death - is paid in the
currency of toxicity. Figure 5 below highlights the incidence of various
toxicities for the Tax-327 and SWOG trials. Petrylak, ibid, concluded
“Treatment with estramustine and docetaxel moderately increases survival
at a cost of an increased rate of adverse events”, i.e., grade 3 and 4
neutropenic fevers, nausea and vomiting, and cardiovascular events - all
significantly more frequent. In an article to be published in the May,
2005, JCO, “Prostate Cancer Chemotherapy: Emerging From the Shadows” Bruce
Roth wrote: “However, comparison of data from the two definitive phase III
trials would suggest that there is likely little, if any, survival benefit
from the addition of estramustine to a docetaxel regimen.
 A
clear indication for chemotherapy is the desire to reduce tumor related
pain, and this is achieved in all these regimens in 25% to 35% of
instances, usually for a duration of 3 to 5 months. In the face of
objective metastateic disease the desire is to
objectively reduce tumor volumes, but this occurs less frequently - in
only about 10% to 17% of cases. If treatment effectiveness can be verified
for agents with less or minimal toxicity - possible examples being
“Atrasentan” (an endothelin A receptor inhibitor), or vaccines (i.e.,
Dendreon’s “Provenge”), then the favorable relationship between benefit
and toxicity will allow intervention earlier in the course of HRPC.
Dr.Tomasz Beer, Oregon
Health & Science University, has piloted several trials to attempt to
maximize benefits while reducing toxicity. His phase II study of
weekly Docetaxel showed a median survival of 10+ months, a PSA response of
44%, a median TTP of ~ 5 months, a measurable disease response of ~ 31%, ,
and a 37% decrease in pain. A follow-up phase II study of weekly
Docetaxel plus high-dose calcitriol produced a median survival of 19.5
months, a median TTP of 11.4 months, and an 81% > 50% PSA decline. The
results of a randomized, double blinded comparison of these two regimens
will be presented at the 2005 ASCO meeting.
The question of the
optimal duration of chemotherapy is also under study. Dr. Eisenberger at
Johns Hopkins has opted for a strategy of treatment until maximal response
followed by a period of observation, and retreatment on relapse. And Dr.
Beer reported his observation on this strategy in British J Cancer 91(8)
2004. Eight of 37 men had a treatment response to PSA < 4 ng/mL and these
eight then had intermittent treatment: 11 months to maximal response
followed by one or more treatment “holidays” of ~ 5 months each. The
overall time from the start of therapy to treatment failure for these
eight men was 26.5 months -and they experienced an associated benefit of
an improved quality of life.
Bottom Line:
An active exploration is underway to find the optimal chemotherapy agents
and best strategy for their implementation in hormone refractory prostate
cancer. The goal is achieveing increased benefit while minimizing
toxicity. An understanding of the natural history of HRPC gives
perspective for evaluating the results of new treatments.
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