VOLUME 26 NUMBER 36 DECEMBER 20 2008

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Phase III Trial of Androgen Ablation With or Without

Three Cycles of Systemic Chemotherapy for Advanced
Prostate Cancer
Randall E. Millikan, Sijin Wen, Lance C. Pagliaro, Melissa A. Brown, Brenda Moomey, Kim-Anh Do,
and Christopher J. Logothetis
From the Departments of Genitourinary
Medical Oncology and Biostatistics,
University of Texas M.D. Anderson
Cancer Center, Houston, TX.
Submitted December 26, 2007;
accepted June 30, 2008; published
online ahead of print at www.jco.org on
November 24, 2008.
Presented in part at the Annual Meeting of the American Urologic Association May 8-13, 2004, San Francisco, CA.
Authors disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Clinical Trials repository link available on
JCO.org.
Corresponding author: Randall Millikan,
PhD, MD, Department of Genitourinary
Medical Oncology, University of Texas
M.D. Anderson Cancer Center, 1155
Pressler, CPB7.3462, Houston, TX
77030; e-mail: rmillika@mdanderson.org.
2008 by American Society of Clinical
Oncology
0732-183X/08/2636-5936/$20.00

Purpose
We conducted a phase III trial in patients with previously untreated metastatic prostate cancer to
test the hypothesis that three 8-week cycles of ketoconazole and doxorubicin alternating with
vinblastine and estramustine, given in addition to standard androgen deprivation, would delay the
appearance of castrate-resistant disease.
Patients and Methods
Eligible patients had metastatic prostate cancer threatening enough to justify sustained androgen
ablation and were fit enough for chemotherapy. The primary end point was time to castrateresistant progression as shown by increasing prostate-specific antigen, new radiographic lesions,
worsening cancer-related symptoms, or receipt of any other systemic therapy.
Results
Three hundred six patients were registered; 286 are reported. Median time to progression was 24
months (95% CI, 18 to 39 months) in the standard therapy arm, and 35 months (95% CI, 26 to 44
months) in the chemohormonal group (P .39). At median follow-up of 6.4 years, overall survival
was 5.4 years (95% CI, 4.7 to 7.8 years) in the standard therapy arm versus 6.1 years (95% CI, 5.1
to 10.1 years; P .41). Prostate-specific antigen kinetics at the time of androgen ablation and the
nadir after hormone treatment were strongly correlated with survival. Chemotherapy significantly
increased the burden of therapy, with 51% of patients experiencing an adverse event of grade 3
or worse, especially thromboembolic events.
Conclusion
There is no role for ketoconazole and doxorubicin alternating with vinblastine and estramustine
before emergence of a castrate-resistant phenotype.

DOI: 10.1200/JCO.2007.15.9830

J Clin Oncol 26:5936-5942. 2008 by American Society of Clinical Oncology

INTRODUCTION

The front-line paradigm for the treatment of metastatic prostate cancer remains, as it has been for
more than half a century, to disrupt androgen
receptor signaling. Despite reliable initial response, all patients eventually exhibit castrateresistant progression, a disease state responsible for
slightly more than 27,000 deaths per year in the
United States.1
Since the early 1970s, scores of phase II studies
found a monotonous median survival of approximately 11 months for patients with castrate-resistant
prostate cancer.2,3 The University of Texas M.D.
Anderson Cancer Center experience with weekly
treatment consisting of ketoconazole and doxorubicin alternating with vinblastine and estramustine (KA/VE), given 6 of 8 weeks, suggested
5936

2008 by American Society of Clinical Oncology

an incremental advance. This regimen produced

obvious palliation in the majority of treated patients, and a median survival of 18 months, with
10% alive at 3 years.4 Similar reports for taxanebased therapy soon appeared5,6 and were confirmed
in a community-based randomized phase II trial.7
More recently, docetaxel has emerged as a useful
single agent, and two large phase III trials have now
rigorously demonstrated a modest survival advantage for docetaxel-based therapy.8,9
Many investigators have considered early application of cytotoxic therapy in an attempt to forestall progression to overt castrate resistance. In fact,
addition of cytotoxics to hormone therapy was first
tested more than 30 years ago, and there are at least
10 published randomized trials of this design, involving more than 1,900 patients (Table 1). None of
these trials included cytotoxic therapy that prolongs

Chemohormonal Therapy for Nonlocalized Prostate Cancer

Table 1. Summary of 10 Published Randomized Trials of Sustained Androgen Ablation With or Without Immediate Chemotherapy

First Author and

Year

No. of
Patients
Reg

Rep

Therapy

Murphy,10 1983

July 1976 to September 1980

Accrual

301

246

Murphy,11 1986

July 1980 to June 1983

319

296

Osborne,12 1990

September 1982 to October 1986

143

137

Pummer,13 1997

April 1988 to January 1991

145

114

Janknegt,14 1997

January 1989 to July 1990

419

385

A: DES, orch; B: DES, CTX; C:

Estramustine, CTX
A: DES or orch; B: CTX/FU/DES;
C: Estramustine
A: DES, orch; B: DES or
orch CTX/dox
A: orch/FLT; B: orch/FLT
epirubicin
A: orch; B: orch estramustine

Fontana,15 1998

June 1990 to May 1993

63

55

Boel,16 1999

June 1988 to December 1991

178

148

A: LHRH superagonist; B:
LHRH mitomycin
A: orch; B: orch mitomycin

de Reijke,17 1999

February 1990 to May 1995

189

184

A: orch; B: orch mitomycin

Kuriyama,18 2001

April 1990 to December 1992

142

136

Noguchi,19 2004

June 1995 to March 1998

57

51

A: DES or orch; B: DES or

orch UFT
A: LHRH superagonist FLT;
B: LHRH estramustine

Median TTP

Median OS

Not reported

21 months in all arms

15 months in all arms

33 months in all arms

A: 15 months; B: 18
months (P .8)
A: 12 months; B: 22
months (P .02)
A: 17 months; B: 24
months (P .3)
A: 19 months; B: 25
months (NS)
A: 29 months; B: 26
months (NS)
A: 12 months; B: 12
months (NS)
A: 30 months; B: 72
months (P .06)
A: 14.6 months; B: 25.4
months (P .03)

A: 26 months; B: 22
months (P .55)
A: 18 months; B: 30
months (P .12)
A: 24 months; B: 27
months (NS)
A: 32 months; B: 29
months (NS)
A: 31 months; B: 31
months (NS)
A: 26 months; B: 22
months (P .04)
A: 5.7 years; B: 8.2
years (P .13)
A: 30 months; B: 30
months (NS)

Abbreviations: Reg, No. of patients registered; Rep, No. of patients reported; orch, bilateral orchiectomy; DES, diethyl stilbestrol; dox, doxorubicin; NS, not
significant; LHRH, super agonist of luteinizing hormonereleasing hormone; CTX, cyclophosphamide; FU, fluorouracil; UFT, uracil plus tegafur (an oral
fluoropyrimidine); FLT, flutamide.

survival in the setting of metastatic castrate-resistant disease, so the

availability of regimens in the mid 1990s that seemed to be more active
suggested to us that it was prudent to revisit the issue of early intervention with what seemed to be better chemotherapy. In particular, we
designed a trial to test the hypothesis that the addition of KA/VE to
standard, sustained, androgen ablation would delay the emergence of
castrate-resistant disease, and ultimately, prolong survival. Here we
report results of this phase III trial in a patient population with nonlocalized prostate cancer felt to be sufficiently threatening to justify
sustained androgen ablation. The primary end point was time to
castrate-resistant progression; secondary end points were overall and
cause-specific survival.
PATIENTS AND METHODS
Patients
Eligible patients had nonlocalized prostate cancer conventionally treated
with sustained androgen ablation and were also fit enough for chemotherapy.
If increasing serum prostate-specific antigen (PSA) after definitive local therapy was the only clinical evidence of metastatic disease, then the PSA doubling
time (PSADT) had to be less than 9 months. Specific eligibility criteria included histologic proof of acinar adenocarcinoma; PSA more than 1.0 ng/mL;
life expectancy from comorbid illness in excess of 3 years; Eastern Cooperative
Oncology Group performance status of 2 or better, an absolute neutrophil
count of at least 1,500/L; platelet count of at least 150,000/L; transaminases
less than 4 the upper limit of normal; an estimated creatinine clearance of at
least 40 mL/min; and no evidence of active ischemia or bifascicular block by
ECG. Patients with a history of vagotomy or who required continuous therapy
with antacids, histamine receptor blockers, or proton pump inhibitors were
excluded, as were patients taking terfenadine, astemizole, omeprazole, or cisapride. Patients were excluded for any history of transient ischemic attack
within the previous 6 months, a requirement for regular antianginal therapy,
or any history of deep venous thrombosis or pulmonary embolism. Prior
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hormone therapy was allowed if it was an adjunct to definitive local therapy,

was given for 6 months or less, and was completed at least 12 months before
initiating therapy for metastatic disease.
All patients provided written informed consent to participate in this trial,
which was approved by the M.D. Anderson Cancer Center institutional review
board, and overseen by the institutional Data Monitoring Committee.
Patients with metastatic prostate cancer are typically started on hormonal therapy before being seen at M.D. Anderson. Accordingly, eligible
patients could be registered up to 3 months from the date hormonal therapy
was initiated, and time-to-event data were calculated from the start of hormonal therapy, not the date of protocol registration.
Treatment
All patients received androgen ablation therapy, either by means of
luteinizing hormonereleasing hormone super-agonist (of any formulation)
or surgical castration. Use of androgen receptor antagonists was suggested in
the protocol but was left to the discretion of the treating physicians. Patients
assigned to the experimental arm also received three cycles of KA/VE, repeated
every 8 weeks: ketoconazole 400 mg orally (PO) three times a day times 7
days/wk in weeks 1, 3, and 5; doxorubicin 20 mg/m2 administered intravenously on days 1, 15, and 29; vinblastine 4 mg/m2 administered intravenously
on days 8, 22, and 35; estramustine 140 mg PO three times a day times 7
days/wk in weeks 2, 4, and 6; and hydrocortisone 20 mg PO every morning and
10 mg PO every evening.
Concurrent use of antiandrogens and ketoconazole was not allowed
secondary to concerns about cumulative hepatic toxicity; therefore, patients
on the experimental arm did not start antiandrogens until after three cycles
of KA/VE.
Clinical End Points
The primary end point was time to castrate-resistant progression, defined by any of the following: symptomatic or radiographic progression, increasing PSA greater than 25% above the nadir on hormonal therapy (or 1
ng/mL for those with a nadir 0.5 ng/mL), or receipt of any additional
therapy. As usual, these progression-defining events required a castrate
testosterone level ( 50 ng/dL) and, if applicable, withdrawal of androgenreceptor blockers.
2008 by American Society of Clinical Oncology

5937

Millikan et al

Descriptive end points included documentation of adverse events (according to the criteria of the National Cancer Institute Common Toxicity
Criteria version 2.0) and documentation of evolution to an anaplastic phenotype, which was declared when any of the following clinical features were
present: lytic bone metastases, hypercalcemia, biopsy-proven neuroendocrine
cytologic features, or symptomatic or radiographic progression occurring
without an increase in PSA concentration.
Statistical Considerations
Patients were randomly assigned (1:1) to two arms, with enforced balance with respect to four prospectively defined strata: high-volume bone or
visceral disease, low-volume bone (ie, one or two areas of presumably pathologic uptake on bone scan), local/nodal with prior definitive local therapy, and
local/nodal without prior definitive therapy. The trial was designed to test the
hypothesis that addition of KA/VE to standard androgen ablation would result
in an improvement in median time to castrate-resistant phenotype from 24
months (the anticipated result from hormone therapy only) to 36 months. The
initial target accrual was 368 patients, providing 80% power to detect this
difference with type I error of 5%. Although arbitrary, a 12-month difference
was considered to have a reasonable likelihood of being associated with a
difference in overall survival and to represent a clinically relevant difference to
most clinicians.
Because the trial was designed in the midst of PSA-driven stage migration, we planned (and performed) a single interim analysis for the purpose of
reassessing the accrual target in view of the actual performance of the control
group. This analysis was performed in 2001, after total accrual of 229 patients.
Given the observed median time to progression (at that time) of 21 months in
the control arm, the accrual goal was revised downward to 300 patients, which
preserved the original target power and type I error.
Fishers exact test20 was used to assess the independence between two
categoric variables. The Wilcoxon rank sum test21 was used to assess whether
there is a difference between two groups for continuous variables. For all
time-to-event data, survival curves were estimated using the Kaplan-Meier
method, and log-rank test was used to assess the difference between groups.
Multivariate analysis was performed using the Cox proportional hazards
regression model 22 to estimate adjusted hazard ratios on overall survival
and progression to castrate-resistant disease. The statistical analyses were carried out using S-Plus 2000 (Insightful Corporation, Seattle, WA) and StatXact
4.0.1 (Cytel Software Corporation, Cambridge, MA). All statistical tests
were two-sided.
The analysis was based on intention to treat but does exclude patients
immediately withdrawing consent, because there are no data for such patients.
Patients who died without evidence of recurrent prostate cancer or were lost to
follow-up before evidence of castrate-resistant progression were censored for
the analysis of time to progression and cause-specific survival. Patients lost to
follow-up after they were confirmed to have progressive, castrate-resistant
disease were treated in the most conservative way (ie, they were counted as
dead as of the day after their last follow-up).

Patients registered and randomly allocated (n = 306)

Hormone therapy only (n = 156)

Chemohormonal therapy (n = 150)

Patients excluded
(n = 7)
Withdrew consent (n=5)
Ineligible
(n=1)
Lost to follow-up
(n=1)

Patients reported (n = 149)

Patients excluded (n = 13)

Withdrew consent (n=12)
Ineligible
(n=1)

Patients reported (n = 137)

RESULTS

Between September 1996 and April 2003, 306 patients were registered
(Fig 1). Of these, 17 patients immediately withdrew consent (related to
dissatisfaction with the arm to which they were randomly assigned).
Two patients were discovered to be ineligible before starting therapy
and were excluded, and one international patient was immediately lost
to follow-up. This leaves 286 patients (93% of those registered) in the
analysis. Baseline characteristics are listed in Table 2. There were no
statistically significant imbalances for any of the baseline covariates considered.
Among 137 patients assigned to the experimental arm, 110 patients (80%) completed three cycles of KA/VE as planned, 20 patients

Table 2. Baseline Characteristics of Patients Included in Analysis

Feature
No. randomly assigned
No. in analysis
Age at diagnosis, years
Median
Range
Time from diagnosis to hormonal
therapy, months
Median
Range
Ethnicity
Hispanic
Non-Hispanic
Race
White
African American
Asian
Prior local therapy
Radical prostatectomy
Aborted prostatectomy
External-beam radiotherapy
Brachytherapy
Cryotherapy
None
PSA at diagnosis, ng/mL
10
10-20
20-100
100
Unknown
PSADT at hormone therapy,
months
Undefined
3
3 to 9
9
Stratification
Local, with prior definitive
therapy
Local, without definitive
therapy
Low-volume bone
High-volume bone/visceral

Hormone Chemohormonal
Rx Group
Rx Group
Total

156
149

150
137

306
286

59
42-80

58
37-78

20
0.3-104

28
0.1-109

15
134

8
129

23
263

8
92

139
8
2

131
6
0

270
14
2

94
5
1

45
6
10
1
1
86

35
5
6
4
0
87

80
11
16
5
1
173

28
4
6
2
0
60

36
27
48
37
1

34
26
42
33
2

70
53
90
70
3

24
19
31
24
1

41
40
44
24

45
44
32
16

86
84
76
40

30
31
26
14

29

22

51

18

25

28

53

19

30
65

26
61

56
126

20
44

Abbreviations: Rx, therapy; PSA, prostate-specific antigen; PSADT, PSA

doubling time.

Fig 1. Enrollment and reporting.

5938

2008 by American Society of Clinical Oncology

JOURNAL OF CLINICAL ONCOLOGY

Chemohormonal Therapy for Nonlocalized Prostate Cancer

Androgen
Ablation Only

Chemohormonal Rx

Event

Grade 3

Grade 4

Grade 3

Grade 4

Abdominal pain
Bone pain
Cardiac ischemia/infarction
Catheter-related infection
Catheter-related thrombosis
Chest pain
CNS ischemia
Depression
Fatigue
Infection
Left ventricular function
Neuropathy
Neutropenia
Neutropenic fever
Odynophagia
Pneumonitis
Sinus bradycardia
Stomatitis
Supraventricular tachycardia
Syncope
Thrombosis/embolism
Ureteral obstruction
Totals

1
0
0
0
0
0
0
0
0
0
0
1
0
0
0
1
0
0
0
1
1
0
5

0
1
2
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
5

3
8
0
3
8
1
1
2
6
15
2
5
6
2
2
1
2
4
1
1
13
0
86

2
1
1
0
1
1
0
1
0
0
0
0
7
0
0
0
0
0
2
0
1
1
18

NOTE. Only events observed in more than one patient with maximum grade
of 3 or 4 are shown. There were no toxic deaths.
Abbreviation: Rx, therapy.

www.jco.org

A
Progression-Free Survival
(probability)

Table 3. Summary of Observed Adverse Events

CI, 18 to 39 months) for the androgen ablation arm, and 35 months

(95% CI, 26 to 44 months) for those receiving chemohormonal therapy (P .39; Fig 2A). Note that the curves happen to artifactually
diverge at the median; the proportional hazards assumption is not
valid for the observed curves.
As expected, extent of disease at the time hormone therapy was
initiated was strongly related to outcome. Among all patients, the
median time to progression was 58.3 months (95% CI, 38 to 120
months) for those with local/regional disease and prior definitive local
therapy, 42.9 months (95% CI, 29 to 89 months) for those with
local/regional disease without prior definitive local therapy, 39.4
months (95% CI, 26 to 120 months) for patients with one or two
lesions by bone scan, and 14.2 months (95% CI, 12 to 20 months) for
patients with three or more bone lesions or involvement of viscera. It is
convenient to combine the first three groups as the low-volume subset
(n 160) and consider the last group (n 126) as the high-volume
subset. In the low-volume subset, the median time to castrate-resistant
progression was 45.4 months (95% CI, 29 to 120 months) for the
control arm and 52.4 months (95% CI, 36 to 86 months) for patients
assigned to the chemohormonal arm (P .94; Fig 2B). In the highvolume subset, the median time to progression was 11.2 months (95%

1.0
Androgen ablation
Chemohormonal

0.8

Median
24
35

95% CI
18 to 39
26 to 44

100

120

0.6

0.4
0.2
P = .39

20

40

60

80

Time from Initiation of Hormone Therapy (months)

No. patients at risk
Androgen ablation
Chemohormonal

B
Progression-Free Survival
(probability)

(15%) completed two cycles, and seven patients (5%) received one
cycle or fewer of treatment. Fatigue and thromboembolic events were
the most common reasons for discontinuation of chemotherapy. Despite our intent for sustained androgen deprivation, 28 patients (19%)
on the standard therapy arm and 67 patients (49%) on the experimental arm are known to have used intermittent androgen ablation, and it
is quite likely that some patients have taken this course of action
unknown to us.
Adverse events observed more than once, and of grade 3 or 4, are
summarized in Table 3. There were no treatment-related deaths.
Overall, 148 events of grade 3 or worse were recorded in 83 patients
(29%). The toxicity observed with KA/VE was substantial: 70 patients
(51%) exposed to KA/VE had at least one grade 3 event, and most were
attributed to treatment. By contrast, only 13 patients (9%) in the
control arm had an adverse event of grade 3 or worse, and most were
considered unrelated to treatment. As anticipated, the most frequently
observed adverse events were thromboembolic, with a total of 23 such
events of grade 3 or worse in the KA/VE arm versus only one event in
the control arm.
The primary end point of the trial was time to castrate-resistant
progression. As of December 2006, 194 patients (68%) had reached
this end point, and another 12 patients (4%) had died without evidence of active prostate cancer. Eighty patients (28% of the total)
remain at risk for progression. Progression was declared by PSA criteria in 122 patients (63%), radiographic criteria in 56 patients (29%),
initiation of therapy in 10 patients (5%), and progressive symptoms in
six patients (3%). Median time to progression was 24 months (95%

77
91

54
52

33
39

20
23

11
5

1.0
Androgen ablation (high volume)
Androgen ablation (low volume)
Chemohormonal (high volume)
Chemohormonal (low volume)

0.8

0.6

0.4
0.2

20

40

60

80

100

120

Time from Initiation of Hormone Therapy (months)

Fig 2. Time to progression (TTP) as defined by appearance of castrate-resistant
phenotype. See text for definition of progression and details of stratification. (A) TTP
by assigned treatment. (B) TTP by treatment, stratified by disease volume at entry.

2008 by American Society of Clinical Oncology

5939

Millikan et al

CI, 10 to 17 months) in the control group and 20.5 months (95% CI,
14 to 30 months) in the experimental arm (P .08; Fig 2B).
We found no evidence that early exposure to chemotherapy
contributes to the evolution of more aggressive cancers, as an anaplastic phenotype developed in five patients in each arm.
Overall, 156 patients (55%) have died, including 142 deaths
resulting from prostate cancer and 14 deaths from unrelated causes.
Median follow-up for survival was 6.4 years. Median overall survival
for patients in the control arm was 5.4 years (95% CI, 4.7 to 7.8 years),
versus 6.1 years (95% CI, 5.1 to 10.1 years) for patients receiving
KA/VE (P .41; Fig 3A). In the low-volume subset, the median
survival in the hormone therapy arm was 7.8 years (95% CI, 5.5 to 10.1
years) versus 7.8 years (95% CI, 6.9 to 10.1 years) among patients
treated initially with KA/VE (P .68; Fig 3B). In the high-volume
subset, the median survival in the hormone therapy arm was 3.1 years
(95% CI, 2.6 to 5.5 years), versus 4.4 years (95% CI, 3.2 to 6.1 years)
among patients treated initially with KA/VE (P .29; Fig 3B).
Survival from the date of progression was virtually identical in the
two arms, with a median value of 26 months. Nearly all patients (in
either arm) did receive cytotoxic therapy for castrate-resistant disease,
usually including a taxane.
A standard Cox model including indicators for treatment arm,
prior definitive local therapy, age, disease volume stratum, nadir

1.0
Androgen ablation
Chemohormonal

Median
95% CI
65
56 to 93
74
61 to 120+

Overall Survival
(probability)

0.8

0.6

0.4

0.2
P = .41

20

40

60

80

100

PSA,23,24 PSA at entry, and PSADT24 before initiation of hormone

therapy was fitted to both the time-to-progression and survival data.
All of these covariates remained significant in the multivariate model,
except age and treatment arm. The most powerful predictor for both
outcomes was achievement of PSA less than 0.2 ng/mL at 8 months
from initiation of hormone therapy (Fig 4).
We had sufficient PSA data before the initiation of androgen
ablation to calculate PSADT for 200 patients (70%). Patients with a
PSADT less than 3 months (n 84) had median time to progression
of 16 months (95% CI, 14 to 25 months), compared with 46 months
(95% CI, 36 to 74 months) for 116 patients with PSADT of 3 months
or longer (P .0001). The corresponding values for cause-specific
survival were 3.5 years (95% CI, 3.2 to 5.5 years) in the short PSADT
group versus 7.8 years (95% CI, 6.2 to 10.1 years) for those with a long
PSADT (P .0001). Among these 200 patients, there was no hint of
any difference in outcome according to assigned treatment after accounting for PSADT at baseline.
DISCUSSION

At first blush, our primary result of a difference in median time to

progression of 11 months may seem provocative, despite the fact that
the P value for this result is far from significance. There are three
concerns: the trial could simply be underpowered for a difference of
this magnitude; baseline covariates could be nonrandomly distributed; or the median values could be poor surrogates for the information in the survival curve. Taking the last point first, we know that the
proportional hazards assumption is not met, and it is clear from
inspection that the separation at the median is not representative of
the overall difference in the curves. Furthermore, any hint of difference disappears with covariate adjustment in the Cox model. Finally,
even though this was a small trial, we did have reasonable power to
find a difference of this magnitude. Under the usual assumptions, the
power to detect the difference we observed was approximately 78%,
and, in the high-volume subset (n 126), we have 82% power to
detect the observed difference of median time to progression (11.2 v

120

Time from Initiation of Hormone Therapy (months)

135
125

92
92

55
58

1.0

Overall Survival
(probability)

0.8

27
32

12
7

1.0

Androgen ablation (high volume)

Androgen ablation (low volume)
Chemohormonal (high volume)
Chemohormonal (low volume)

0.8

0.6

Overall Survival
(probability)

No. patients at risk

Androgen ablation
Chemohormonal

PSA Nadir Median

> 0.2
31
0.2
120+

95% CI
29 to 37
94 to 120+

0.6

0.4

0.2

0.4

P < .0001

0.2

20

40

60

80

100

120

Time from Initiation of Hormone Therapy (months)

0

20

40

60

80

100

120

Time from Initiation of Hormone Therapy (months)

Fig 3. Overall survival. See text for details of stratification. (A) Survival by assigned
treatment. (B) Survival by treatment, stratified by disease volume at entry.
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2008 by American Society of Clinical Oncology

No. patients at risk

Nadir > 0.2
Nadir 0.2

49
86

16
76

4
51

2
25

1
11

Fig 4. Overall survival among all patients by prostate-specific antigen (PSA) nadir
after androgen ablation.
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Chemohormonal Therapy for Nonlocalized Prostate Cancer

20.5 months) at a significance level of .05. Thus it is clear that there is

no hint of improved outcome with KA/VE. In fact, in retrospective,
exploratory analyses, we examined subsets with short PSADT, young
age, extensive disease, and a short interval from diagnosis to hormonal
therapy and found no subset where early application of KA/VE improves outcome.
Importantly, our results provide documentation of outcome in
the modern era. For example, patients with only regional disease after
prior local therapy had an estimated cause-specific survival of 70% at
6 years. Even among patients with small-volume bone involvement
(ie, one or two lesions on bone scan), only 33 (59%) of 56 patients have
experienced disease progression, and just 25 patients (45%) have died
of prostate cancer. The estimated median cause-specific survival of
this cohort exceeds 7 years.
Our results also confirm the prognostic implications of PSADT
when hormonal therapy is initiated24 and the prognostic importance
of a clinical response to androgen ablation.23,24 Not only did PSA nadir
after hormone therapy correlate with subsequent time to progression,
but the duration of hormonal response was the most powerful predictor of survival after progression to a castrate-resistant phenotype, as we
have previously reported.7
Our results were mildly surprising, given the fact that the response rate and modest survival prolongation seen with KA/VE applied to patients with far advanced disease are similar to treatment
effects seen in patients with metastatic colon or breast cancer. Importantly, however, in those diseases, the benefit of early (ie, adjuvant)
therapy is well established, but a corresponding effect in prostate
cancer has not been observed. This suggests to us that sensitivity to
chemotherapy is a function of how far the cancer has evolved toward
castrate resistance. In keeping with this notion, the time to progression
observed in this trial was significantly delayed in the high-volume
group but not in those with less advanced disease. The hypothesis that
hormone-dependent prostate cancers are resistant to chemotherapy
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AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS
Conception and design: Randall E. Millikan, Lance C. Pagliaro,
Christopher J. Logothetis
Financial support: Christopher J. Logothetis
Administrative support: Randall E. Millikan, Christopher J. Logothetis
Provision of study materials or patients: Randall E. Millikan, Lance C.
Pagliaro, Christopher J. Logothetis
Collection and assembly of data: Randall E. Millikan, Melissa A. Brown,
Brenda Moomey
Data analysis and interpretation: Randall E. Millikan, Sijin Wen,
Kim-Anh Do
Manuscript writing: Randall E. Millikan, Christopher J. Logothetis
Final approval of manuscript: Randall E. Millikan, Sijin Wen, Lance C.
Pagliaro, Melissa A. Brown, Brenda Moomey, Kim-Anh Do,
Christopher J. Logothetis

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