Full text of DOI:10.1016/S0022-5347(05)67647-1

0022-5347/00/1635-1481/0
®
THE JOURNAL OF UROLOGY
Vol. 163, 1481–1485, May 2000
Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Printed in U.S.A.
PROSTATE SPECIFIC ANTIGEN RESPONSE TO MITOXANTRONE AND
PREDNISONE IN PATIENTS WITH REFRACTORY PROSTATE CANCER:
PROGNOSTIC FACTORS AND GENERALIZABILITY OF A MULTICENTER
TRIAL TO CLINICAL PRACTICE
ANTHONY J. DOWLING,* PIOTR M. CZAYKOWSKI, MURRAY D. KRAHN,*,† MALCOLM J. MOORE
AND IAN F. TANNOCK*,†
From the Department of Medical Oncology and Hematology, Princess Margaret Hospital and Department of Medicine, Laboratory
Medicine and Pathobiology, Program in Clinical Epidemiology and Health Sciences Research, University of Toronto, Toronto, and Fraser
Valley Cancer Centre, British Columbia Cancer Agency, Surrey and University of British Columbia, Vancouver, British Columbia,
Canada, and Department of Oncology, St. Vincent’s Hospital, Fitzroy, Melbourne, Australia
ABSTRACT
Purpose: We determine prostate specific antigen (PSA) response and durability, and prognostic
factors associated with response and survival in patients with symptomatic hormone refractory
prostate cancer treated with mitoxantrone and prednisone at a single institution. We then
compare the results with those of a randomized phase III clinical trial.
Materials and Methods: A retrospective review of all 133 patients treated with mitoxantrone
and prednisone at Princess Margaret Hospital since 1994 was performed. PSA response and
duration, and overall survival were determined as well as the influence of baseline factors on
these outcome parameters. Results were compared to those for patients randomized to receive
mitoxantrone and prednisone in the Canadian clinical trial which demonstrated palliative
benefit of this regimen.
Results: Patients treated after trial closure had shorter survival (p ϭ 0.003) but represented
a poorer prognosis cohort. PSA response of the trial and post-trial cases was 34% and
28%, respectively (p ϭ 0.36), and median duration of response was 118 and 175 days or greater,
respectively. Factors predictive of PSA response in the nontrial cohort were longer time from
diagnosis of prostate cancer (p ϭ 0.027) and higher baseline PSA (p ϭ 0.013). Factors predictive
of increased survival in both groups were younger age (p Ͻ0.04), better baseline Eastern
Cooperative Oncology Group performance status (p Ͻ0.02), and higher hemoglobin (p Յ0.05) and
PSA response (p Ͻ0.0001). Gleason score was not predictive of response or survival.
Conclusions: Although patients treated outside of the trial had poorer prognostic features,
rates of PSA response to mitoxantrone and prednisone were comparable. Factors predictive of
survival were similar in the 2 cohorts. Results of the randomized trial are generalizable to clinical
practice.
KEY WORDS: prostate-specific antigen, prostatic neoplasms, drug therapy, prostate, mitoxantrone
Adenocarcinoma of the prostate is the most common ma- tients with hormone refractory prostate cancer compared to
prednisone alone.2 Mitoxantrone was selected for this study
due to its tolerability and low toxicity in older patients. In the
trial 38% of patients receiving mitoxantrone and prednisone
had stringently measured reductions in pain and/or analge-
sic intake, without an increase in the other parameter, com-
pared to 21% treated with prednisone alone (p ϭ 0.025).2
Median duration of a palliative response and time to symp-
tomatic progression were significantly longer for patients
receiving mitoxantrone and prednisone, and improvement in
various aspects of quality of life was also sustained for longer
periods.3 Evaluation of PSA response was not a predeter-
mined end point of the Canadian trial but palliative response
and PSA response were correlated, albeit imperfectly. PSA
response is a useful marker of antitumor activity, although it
does not necessarily imply benefit from the use of systemic
therapy.
lignancy in men and the second leading cause of male cancer
deaths in North America.1 Unless they die of other causes, in
all patients with recurrent or metastatic prostate cancer
progression to hormone independence inevitably occurs. Hor-
mone refractory prostate cancer is accompanied by clinically
important symptoms, such as pain and fatigue, and almost
invariably increasing serum prostate specific antigen (PSA).
As hormone refractory prostate cancer is incurable the pri-
mary goal of management is to palliate symptoms. A funda-
mental component of palliation is the regular use of narcotic
analgesics titrated to obtain maximum pain control, given
with agents to alleviate constipation. Radiotherapy is useful
for treatment of dominant sites of pain but after treatment
other areas often become painful. Thus, there is a need for
systemic therapies which relieve symptoms but do not have
toxic effects that lead to deterioration of quality of life.
In a Canadian randomized phase III trial of 161 patients
chemotherapy consisting of mitoxantrone and prednisone
was shown to provide better palliation to symptomatic pa-
Another phase III trial of the use of mitoxantrone with
hydrocortisone compared to hydrocortisone alone in men
with hormone refractory prostate cancer has been reported
recently.4 This trial also included assessment of quality of
life, with some domains, particularly better pain control,
favoring the combined treatment arm. PSA response rates
Accepted for publication December 3, 1999.
* Financial interest and/or other relationship with Immunex Corp.
† Financial interest and/or other relationship with Zeneca.
1481

1482
PROSTATE SPECIFIC ANTIGEN RESPONSE TO MITOXANTRONE AND PREDNISONE
were similar to those in the Canadian trial as 38% of patients defined as time from start of treatment to the first of 2 or
in the combined arm had a 50% or greater decrease compared more PSA values that were lower than baseline by 50% or
to baseline versus 22% of those receiving hydrocortisone greater. Duration of PSA response was defined as the inter-
alone (p ϭ 0.008) and there was no difference in survival val from this time until the last PSA value that was lower
between the 2 treatment arms in either trial. On the basis of than baseline by 50% or greater. Duration of PSA response
these and other data the Food and Drug Administration was censored at the date of the last measured serum PSA for
approved the use of mitoxantrone with corticosteroids for patients who were still responding.
treatment of hormone refractory prostate cancer.
Differences in basic demographic details and PSA response
It is recognized that patients treated in clinical trials often between the 2 cohorts were compared using the chi-square or
have a superior outcome to similar patients treated outside of Fisher’s exact test.8 Survival was compared using the log
a clinical trial, which is probably due to selection factors rank test applied to Kaplan-Meier survival curves.9 Baseline
imposed by entry criteria as well as biases of physicians and factors were examined for influence on PSA response using
patients.5–7 Therefore, it is important to determine whether univariate logistic regression analysis, and these factors plus
benefit observed in clinical trials is maintained when similar PSA response were evaluated for influence on survival using
treatment is used in a nontrial setting. Symptomatic patients Cox proportional hazards model for univariate and multivar-
with hormone refractory prostate cancer have been treated at iate analyses, with backward selection for the latter.8 Base-
Princess Margaret Hospital with mitoxantrone and pred- line variables consisted of ECOG performance status (0, 1, 2
nisone since closure of the trial and, therefore, we evaluated or 3), time from diagnosis of prostate cancer (continuous
the effects of this regimen. Detailed studies of pain relief and variable), hemoglobin (continuous variable), alkaline phos-
quality of life were not available for the followup population. phatase (continuous variable), serum PSA (continuous vari-
We compared PSA response, recognizing that this is a useful able), age (continuous variable), Gleason score (well differen-
marker of anticancer activity but an imperfect surrogate for tiated 2–4, moderately differentiated 5–7 and poorly
palliative benefit and survival.
differentiated 8–10) and dichotomized PSA response (yes/
no). It is noteworthy that continuous variables were included
in the analysis to avoid loss of potential prognostic value
through the use of arbitrary cutoffs. Baseline PSA was ob-
PATIENTS AND METHODS
The study included 133 patients with hormone refractory tained within 4 weeks of commencement of mitoxantrone and
prostate cancer who started treatment with mitoxantrone prednisone. Analysis of factors predicting for PSA response
and prednisone at Princess Margaret Hospital from 1994 to and survival was performed only for cases with complete
March 1998. These patients did not participate in a clinical data. Correlation between factors included in the prognostic
trial. All patients had metastatic prostatic adenocarcinoma factors analysis was assessed by calculating the Pearson
and almost all were symptomatic. Treatment consisted of a correlation coefficient.8 All tests were 2-tailed and all statis-
planned dose of 12 mg./m.2 mitoxantrone every 3 weeks and tical analyses were performed with computer software.
5 mg. oral prednisone twice daily. All patients were followed
until death or censored at the date of last contact or study
RESULTS
closure on October 31, 1998.
Patient characteristics at start of treatment with mitox-
Charts of 132 cases (1 chart was lost) were reviewed ret-
antrone and prednisone are listed in table 1. As patients
rospectively by 1 investigator (A. J. D.). Demographic infor-
treated in the trial were evaluated prospectively as defined
mation, date of prostate cancer diagnosis, tumor character-
by a protocol, whereas the post-trial cohort was not, those
istics, details of hormonal therapy, serum PSA (baseline, on
treated since trial closure were more likely to have worse
treatment and after treatment), baseline alkaline phospha-
tase, baseline hemoglobin and date of last followup or death
were extracted directly from the chart. Almost all serum PSA
TABLE 1. Patient characteristics
levels were assayed at the Princess Margaret Hospital using
Trial
Post-Trial*
133
the microparticle enzyme immunoassay. Baseline Eastern
Cooperative Oncology Group (ECOG) performance status
was estimated from the clinical progress notes at the com-
mencement of chemotherapy. For patients without a date of
death recorded in the chart or for whom there were no cur-
rent progress notes, the referring physician was called to
confirm that the patient was alive or to establish the date of
death. Additionally, the Ontario Cancer Registry was re-
viewed for all patients not known to have died or who were
not on active followup to ensure that no deaths had been
missed. The registry receives notification of all cancer deaths
in the province of Ontario and has updated information to
July 1998.
No. pts.
80
19
61
69
No. Princess Margaret Hospital pts.
133
0
No. other pts.
Median age (range)
(63–75)
70
(64–74)
Mean yrs. from diagnosis
3.0 (1.6–5.1)
3.6 (1.8–6.3)
(interquartile range)
Median ␮g./l. serum PSA
166 (66–678)
388 (115–1150)
(interquartile range)†
% Metastases sites:
Bone
Lymph node‡
98
22
4
95
35
20
5
Visceral‡
Other
9
% ECOG status:‡
0
6
57
26
10
0
15
62
23
1
The primary end point of this analysis was PSA response
based on intent to treat. PSA response was defined as a
decrease in serum PSA by at least 50% compared to baseline,
maintained on at least 2 occasions each at least 3 weeks
apart. This definition differs slightly from the recommenda-
tion of a recent workshop organized by investigators from the
Medicine Branch of the National Cancer Institute, when a
minimal interval of 4 weeks was suggested. Minimum inter-
val between measurements in our study was 3 weeks, at
which time patients received successive courses of chemo-
therapy and serum PSA was evaluated. All patients with
failure to achieve a PSA response as defined previously,
including those with less than 3 serum PSA evaluations,
were regarded as nonresponders. Time to PSA response was
2
3
% Current hormonal therapy:§
Orchiectomy
57
19
55
34
Luteinizing hormone-releasing
hormone࿣
Nonsteroidal antiandrogens‡
Cyproterone acetate‡
Other‡
30
25
9
6
2
1
Gleason score was not available in the trial cohort, and was 2–4 for 9, 5–7 for
57, 8–10 for 48 and unknown for 19 patients in the post-trial cohort.
* Chart was missing for 1 patient.
† Baseline PSA was available for 78 trial and 123 post-trial patients.
‡ Significantly different at p Ͻ0.005 (Fisher’s exact test).
§ Some patients in the trial continued on combined androgen blockade.
࿣ Significantly different at p ϭ 0.05 (Fisher’s exact test).

PROSTATE SPECIFIC ANTIGEN RESPONSE TO MITOXANTRONE AND PREDNISONE
1483
performance status (ECOG 2 and 3) compared to those
TABLE 2. Univariate analysis of factors predicting for PSA
response
treated as part of the trial (85% versus 36%), and were more
likely to have visceral disease (20% versus 4%). Fewer pa-
tients were on combined androgen blockade in the followup
cohort compared to the trial, and cyproterone acetate was
prescribed less commonly. It has been the policy at Princess
Margaret Hospital to discontinue antiandrogen treatment in
patients who are not responding to combined androgen block-
ade and to follow them for at least 1 month before initiating
chemotherapy, unless health is deteriorating rapidly. Base-
line hemoglobin, alkaline phosphatase, serum PSA and time
from diagnosis were obtained for at least 96% of all patients
treated in the trial but Gleason score was not recorded. In the
post-trial cohort Gleason score (on a biopsy obtained at diag-
nosis for all but 3 patients) was available for 86% of patients.
Other baseline factors were available for at least 92% of
patients.
p Value
Factor
Trial
0.57
Post-Trial
Older age
0.72
Higher Gleason score
Not available
0.16
0.46
Longer time from diagnosis
Higher ECOG performance status†
Higher hemoglobin
Higher alkaline phosphatase
Higher baseline PSA
0.027*
0.24
0.50
0.70
0.013‡
0.42
0.47
0.075
0.8
Odds ratio greater than 1 indicates that for an increasing level of the factor
there is an increasing likelihood of PSA response.
* Odds ratio 1.0004 (95% CI 1.000 to 1.0007).
† Higher ECOG performance status indicates inferior performance status.
‡ Odds ratio 1.0005 (95% CI 1.0001 to 1.008).
Fewer cycles of mitoxantrone were given to patients
treated since closure of the trial (median 3 cycles, range 1 to
17) than during the trial (median 6, range 1 to 16). The
proportion of patients receiving mitoxantrone and pred-
nisone who achieved PSA response in the clinical trial was
34% (27 of 80) and for patients treated since trial closure it
was 28% (37 of 133). The difference between these response
rates is not statistically significant (p ϭ 0.35). Rates might be
slight underestimates since patients with missing PSA data
were included as nonresponders. Median time to achieve a
PSA response was 49 days (range 21 to 224) for the trial and
42 days (range 19 to 188) for the post-trial cohort. This time
corresponded to approximately that when patients were un-
dergoing cycle 3 of chemotherapy. Trial data did not permit a
meaningful analysis of the duration of PSA response as 24 of
27 patients were still responding at study closure. As per
trial protocol, once patients receiving mitoxantrone no longer
satisfied criteria for palliative response they could be re-
moved from the study2 and serum PSA was no longer re-
corded. In the post-trial cohort serum PSA was available for
the majority of patients after completion of the course of
mitoxantrone, and 62% (23 of 37) had increasing PSA values
that satisfied criteria for the end of a PSA response. With
these aforementioned caveats, median duration of PSA re-
sponse was 118 days or greater (range 20 to 392) for the trial
and 175 days or greater (range 21 to 616) for the post-trial
cohort.
The combination of mitoxantrone and prednisone was well
tolerated and relatively nontoxic in the trial.2 Treatment
rarely caused nausea and vomiting, and patients required
only prochlorperazine as an antiemetic before mitoxantrone
administration. In the post-trial cohort nadir blood counts
were obtained routinely during only the first cycle of therapy.
There was 1 documented case of Pseudomonas aeruginosa
septicemia following the first cycle of treatment. The patient
fully recovered, received no further chemotherapy and died 8
months later. No other episodes of sepsis were documented,
although evaluation of toxicity was less exhaustive in the
post-trial setting, with some patients returning to the care of
the referring or family physician. Cardiotoxicity may occur
following multiple cycles of mitoxantrone, usually at a cumu-
lative dose of 140 mg./m.2 or greater. Of the 9 patients who
received 10 cycles of mitoxantrone (cumulative dose 120 mg./
m.2) only 2 received more than 140 mg./m.2. Scrutiny of the
charts of these 9 patients revealed that one who was re-
treated after development of symptoms refractory to all other
measures and received a cumulative dose of 228 mg./m.2
mitoxantrone had clinically detectable cardiac compromise at
the time of death from advanced prostate cancer. Another
patient with end stage prostate cancer who had no previously
known cardiac symptoms died suddenly at home of what was
thought to be a massive myocardial infarction.
baseline PSA (p ϭ 0.013) and longer time from diagnosis of
prostate cancer (p ϭ 0.027) were predictive but only in the
post-trial cohort. Gleason score did not predict for PSA re-
sponse in the post-trial cohort (p ϭ 0.46). Due to the rela-
tively low numbers of patients who attained PSA response in
both cohorts, paucity of factors that were statistically signif-
icant in predicting response in univariate analysis and po-
tential danger of creating a model that over fitted the data, a
multivariate analysis examining factors that predicted for
PSA response was not performed.
Univariate and multivariate analyses of factors predictive
of adverse survival in the trial and post-trial cases are shown
in table 3. It is noteworthy that neither baseline PSA level
nor Gleason score at diagnosis was predictive of survival at
this stage of disease. Younger age, better performance status,
higher hemoglobin level and, especially, PSA response were
predictive factors for improved survival. Hazards ratios ob-
tained by multivariate analysis were similar between co-
horts, suggesting good concordance, and some differed only
marginally from unity, reflecting the continuous nature of
the variables. Correlation between factors was examined to
determine whether it could influence the results of multivar-
iate analysis and, generally, expected associations were
found. For example there was a negative correlation between
Gleason score and baseline PSA (r ϭ Ϫ0.227, p Ͻ0.05), and
hemoglobin and alkaline phosphatase (r ϭ Ϫ0.301, p Ͻ0.01).
There was also a strong negative correlation between time
from diagnosis to initiation of chemotherapy and initial Glea-
son score (r ϭ Ϫ0.329, p Ͻ0.01), which was not surprising.
However, it does not provide any further insight into the lack
of prognostic value of Gleason score on survival after subse-
quent chemotherapy.
The figure shows Kaplan-Meier survival curves for the 2
cohorts. Only 1 patient from the trial and 11 from the post-
trial cohort were censored. All remaining patients from both
cohorts were confirmed dead, with the overwhelming major-
ity of deaths due to prostate cancer. In the post-trial cohort 6
patients were alive at study closure and 5 were lost to fol-
lowup. All patients lost to followup in this cohort were in an
advanced palliative state and 3 were known to have returned
to the country of origin to die. Median survival was 11.1
months (95% confidence interval [CI] 8.3 to 13.9) for the trial
cohort versus 7.5 months (95% CI 6.0 to 8.9) for patients
treated subsequently (log rank test for comparison of sur-
vival curves p ϭ 0.003).9 When survival was corrected for the
imbalance in ECOG performance status using the Cox mod-
el9 there was no longer any statistical difference in survival
between the 2 cohorts (p ϭ 0.42).
DISCUSSION
Patients with hormone refractory prostate cancer treated
Univariate analysis of factors predictive of PSA response in with mitoxantrone and prednisone since the closure of the
the trial and post-trial cohorts is shown in table 2. Higher Canadian trial had inferior survival compared to the trial

1484
PROSTATE SPECIFIC ANTIGEN RESPONSE TO MITOXANTRONE AND PREDNISONE
TABLE 3. Factors predicting for overall survival
Trial
Post-Trial
Factor
Hazards Ratio
(95% CI)*
Hazards Ratio
(95% CI)*
p Value
p Value
Univariate analysis:
Older age
0.15
Not available
0.6
1.02
(0.99–1.05)
0.04
0.94
1.002
(1.001–1.06)
(0.72–1.35)
(0.99–1.00)
(1.32–2.50)
(0.97–0.99)
Higher Gleason score
Longer time from diagnosis
Higher ECOG performance status†
Higher hemoglobin
Higher alkaline phosphatase
Higher baseline PSA
PSA response
0.99
0.99
1.82
0.98
1.0
1.44
0.98
(0.99–1.00)
(1.05–1.97)
(0.96–0.99)
0.03
0.02
0.0003
0.0003
0.02
0.74
Ͻ0.0001
0.005
0.005
1.001 (1.0002–1.001)
1.00 (0.99–1.0002)
0.35
1.0004 (1.000–1.001)
1.000
0.41
0.8
(0.99–1.000)
(0.27–0.62)
Ͻ0.0001
(0.21–0.58)
Multivariate analysis:
Older age
Higher ECOG performance status†
Higher hemoglobin
0.009
0.02
0.008
1.05
1.60
0.98
(1.01–1.08)
(1.08–2.37)
(0.96–0.99)
0.04
0.004
0.05
1.03
1.79
0.99
(1.00–1.06)
(1.20–2.65)
(0.98–1.00)
Higher alkaline phosphatase
PSA response
Not significant
Ͻ0.0001
0.008
Ͻ0.0001
1.0002 (1.0002–1.001)
0.29 (0.18–0.46)
0.24
(0.13–0.43)
* Ratio greater than 1 indicates worse survival for increasing levels of the factor and less than 1 indicates worse survival for decreasing levels (p Ͼ0.05).
† Higher status indicates inferior performance status.
refractory prostate cancer. It is of paramount importance
that the definition of PSA response be standardized and
evaluated prospectively. Good performance status and high
hemoglobin were also associated with better survival, as
noted by others.10–12 On univariate analyses a greater time
from diagnosis of prostate cancer predicted for PSA response
and overall survival, and a higher baseline PSA predicted for
response but only for the post-trial cohort. Probably a greater
time from diagnosis of prostate cancer is indicative of a more
indolent natural history, as reflected in the negative correla-
tion with Gleason score. It is less apparent why a higher
baseline PSA or a longer time from diagnosis of prostate
cancer should predict for PSA response.
To our knowledge no previous reports have evaluated
Gleason score as a predictor of PSA response or survival. In
our analysis it predicted for neither, suggesting that once
disease becomes hormone refractory, the histological differ-
entiation of adenocarcinoma has little if any bearing on out-
come (survival or PSA response). It would be interesting to
include initial and later Gleason scores in our analyses but,
unfortunately, this was not possible as few patients have
undergone repeat biopsy. Prior analyses that have assessed
factors predicting for survival have tended to use patients
participating in phase II clinical trials when higher numbers
have measurable soft tissue disease which may not be rep-
resentative of typical patients with prostate cancer.10–12 Me-
dian survival of both cohorts is in keeping with what has
been described previously for cohorts of patients with hor-
mone refractory prostate cancer participating in clinical tri-
als that include those with predominantly bone metasta-
ses.4, 13
We were unable to assess palliative response, as defined by
improvement in pain in the clinical trial, at routine clinic
visits. Improvement in pain is a more direct measure of
palliation, although we have found that PSA response and
palliative response are correlated, albeit imperfectly. The
National Institute of Canada is currently conducting a sec-
ond generation, double-blind, placebo controlled, randomized
phase III clinical trial of mitoxantrone and prednisone, with
or without clodronate, in symptomatic patients with hormone
refractory prostate cancer. That trial has palliative response
and survival as primary end points, and PSA response as a
secondary end point. Analysis of the results of that trial
should provide further information about the relationship
between PSA and palliative response evaluated prospec-
tively.
Kaplan-Meier overall survival of patients treated with mitox-
antrone and prednisone (M ϩ P).
cohort. This finding could largely be explained by the adverse
prognostic factors, in particular advanced ECOG perfor-
mance status. The inferior performance status of patients in
the post-trial cohort also most likely explains why they re-
ceived fewer cycles of chemotherapy. Patients included in
clinical trials often have better outcome than those treated
off study, even when matched for grade and stage of dis-
ease,5–7 and our experience confirms that general observa-
tion. However, despite treatment of patients with poorer
prognosis, comparable PSA responses and median times to
achieve PSA response were seen between our cohort and
those recruited previously for the Canadian trial. Median
PSA response duration in patients attending routine clinic
visits in the post-trial cohort was likely to be a reflection of
the durability of PSA response to mitoxantrone. The majority
had increasing PSA recorded after the response, whereas
further evaluations of PSA were not performed for many
patients in the trial.
PSA response was the most significant factor in univariate
and multivariate analyses that predicted for survival. This
finding does not necessarily imply a cause and effect rela-
tionship, since unknown factors might predict for PSA re-
sponse and longer survival. However, it does lend support to
the hypothesis that PSA response may be an appropriate end
CONCLUSIONS
Comparable rates of PSA response for the post-trial cohort
point in trials evaluating agents in patients with hormone and patients treated on trial support the hypothesis that

PROSTATE SPECIFIC ANTIGEN RESPONSE TO MITOXANTRONE AND PREDNISONE
1485
results of the Canadian randomized phase III clinical trial
are generalizable to those with symptomatic hormone refrac-
tory prostate cancer seen at oncology clinics. Treatment with
mitoxantrone and prednisone is reasonable for patients with
hormone refractory prostate cancer and generalized symp-
toms.
The authors review their experience with a chemotherapy regimen
of mitoxantrone and prednisone in patients with hormone refractory
prostate cancer treated at their institution, and compare the results
to a large multicenter clinical trial. The trial resulted in Food and
Drug Administration approval of mitoxantrone and prednisone for
palliation of advanced prostate cancer (reference 2 in article). There
are a number of important messages in this review. The large clinical
trial resulted in 38% of patients with symptomatic hormone refrac-
tory prostate cancer experiencing significant reductions in pain and,
thus, improvement in quality of life, compared to only 21% on pred-
nisone alone. This chemotherapy regimen of mitoxantrone and
prednisone is well tolerated, and we call it “gentle chemotherapy.”2
As the authors report, patients in clinical trials often have better
outcomes, primarily because of patient selection and better perfor-
mance status. This finding was substantiated by comparing patients
treated in the large randomized trial to the local experience with
hormone refractory prostate cancer. The analysis of PSA as a surro-
gate marker for outcome is noteworthy. Using a 50% decrease in PSA
documented on 2 occasions 3 weeks apart, there was a correlation in
the institutional as well as the clinical trial study for outcome. Other
predictive factors included baseline performance status as well as
hemoglobin levels, both of which have been recognized in the past as
surrogates for survival. Interestingly, 2 other factors were predic-
tive, that is time from diagnosis of prostate cancer and higher base-
line PSA at treatment with mitoxantrone and prednisone. In this
review initial Gleason score was not predictive of response or sur-
vival. One can speculate as to the relationship of higher baseline PSA
correlating with response as well as time from initial diagnosis.
Regarding baseline PSA, higher levels may reflect a more favorable
differentiation of the refractory state and subsequent response to
second line chemotherapy. Time from diagnosis as a surrogate for
response may be correlated with treatment of the primary tumor.
Patients may fare better when the primary tumor has been ablated
with surgery or radiation and then metastatic disease develops. The
biological explanation is not readily apparent but may be related to
the metastatic phenotype.
No correlation was found with initial Gleason score and ultimate
outcome, once the hormone refractory state was reached. However,
ample clinical evidence exists that relates the initial Gleason score to
outcome with local therapies. The authors suggest that it would be
interesting to include the initial and a later Gleason score in the
analysis but few patients had repeat biopsies. I doubt that would be
helpful or valid since the initial description of the Gleason score was
in untreated patients. Additionally, most metastatic deposits in pa-
tients with hormone refractory prostate cancer tend to exhibit more
anaplastic cell types.
The pivotal trial with mitoxantrone and prednisone resulted in the
approval of this regimen for palliation of hormone refractory prostate
cancer. This report provides further insight into the value of PSA as
a surrogate marker with other predictive factors, including age,
ECOG performance status, hemoglobin, time from initial diagnosis
of prostate cancer and baseline PSA. However, the prognosis for
hormone refractory prostate cancer is still grim, with a median
survival of 9 months. Newer and more innovative therapies need to
be investigated. The data presented here as well as those gleaned
from other phase 2 and phase 3 trials will help us identify surrogate
markers to screen active regimens. Recently the combination of
taxotere and estramustine phosphate has shown significant activity
in hormone refractory prostate cancer. This activity has prompted
the launching of a large intergroup trial in hormone refractory pros-
tate cancer comparing the gold standard of mitoxantrone and pred-
nisone to this new and promising regimen. Quality of life and sur-
vival will be end points in this clinical trial.
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EDITORIAL COMMENT
Nearly 40,000 men will die this year of prostate cancer and most of
these deaths are from hormone refractory disease. The complexion of
hormone refractory prostate cancer has undergone a dramatic trans-
ition in the last few years. Most clinicians consider patients with
hormone refractory prostate cancer as those with primary hormonal
manipulation failure and progression, manifested primarily by dete-
rioration in performance status and pain. With the increase in num-
ber of patients receiving and subsequently having failure of local
therapies, we are witnessing a new type of hormone refractory pros-
tate cancer. The typical patient has local therapy and experiences
biochemical failure (with a lack of demonstrable disease on bone
scan), and undergoes primary hormonal manipulation. The patient
may continue on hormone therapy for years only to experience a
secondary PSA increase representing an early manifestation of hor-
mone refractory prostate cancer. It is not unusual for these men to
still have a negative bone scan, no pain and excellent performance
status yet be refractory to hormones. For lack of a better term, we
have labeled these cases as disease stage D2.5.1
E. David Crawford
Division of Urology
University of Colorado
Denver, Colorado
1. Crawford, E. D. and Blumenstein, B. A.: Proposed substages for
metastatic prostate cancer. Urology, 50: 1027, 1998
2. Personal communication, 1999