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n e w e ng l a n d j o u r na l
of
m e dic i n e
original article
A bs t r ac t
Background
From the Departments of Surgical Sciences
(A.B.-A., M.H.) and Immunology, Genetics, and Pathology (C.B.), and the Regional
Cancer Center Uppsala rebro (L.H., H.G.),
Uppsala University Hospital, Uppsala, the
School of Health and Medical Sciences,
rebro University and Department of Urol
ogy, rebro University Hospital, rebro
(S.-O.A., O.A., J.-E.J.), the Department of
Urology, Linkping University Hospital,
Linkping (A.S.), the Department of Oncology and Pathology, Division of Clinical
Cancer Epidemiology (G.S.), and Department of Medical Epidemiology and Biostatistics (J.P., H.-O.A.), Karolinska Institutet,
Stockholm, and the Division of Clinical
Cancer Epidemiology, Sahlgrenska Academy, Gothenburg (G.S.) all in Sweden;
Kings College London, School of Medicine, Division of Cancer Studies, London
(L.H., H.G.); Channing Laboratory, Department of Medicine, Brigham and Womens
Hospital and Harvard Medical School
(J.R.R.), and the Department of Epidemiology, Harvard School of Public Health
(J.R.R., H.-O.A.) all in Boston; and the
Department of Urology, Helsinki University Central Hospital (K.T.), and the Department of Pathology, University of Helsinki (S.N.) both in Helsinki. Address
reprint requests to Dr. Bill-Axelson at the
Department of Urology, Uppsala University Hospital, 75185 Uppsala, Sweden, or
at anna.bill.axelson@akademiska.se.
Drs. Bill-Axelson and Holmberg contributed equally to this article.
N Engl J Med 2014;370:932-42.
DOI: 10.1056/NEJMoa1311593
Copyright 2014 Massachusetts Medical Society.
932
Radical prostatectomy reduces mortality among men with localized prostate cancer;
however, important questions regarding long-term benefit remain.
Methods
Between 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the
end of 2012. The primary end points in the Scandinavian Prostate Cancer Group
Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer,
and the risk of metastases. Secondary end points included the initiation of androgendeprivation therapy.
Results
During 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the
348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group
and 99 in the watchful-waiting group were due to prostate cancer; the relative risk
was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the absolute
difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed
to treat to prevent one death was 8. One man died after surgery in the radicalprostatectomy group. Androgen-deprivation therapy was used in fewer patients
who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI,
17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer
was largest in men younger than 65 years of age (relative risk, 0.45) and in those
with intermediate-risk prostate cancer (relative risk, 0.38). However, radical prostatectomy was associated with a reduced risk of metastases among older men
(relative risk, 0.68; P=0.04).
Conclusions
Me thods
Patients
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The
n e w e ng l a n d j o u r na l
of
m e dic i n e
but were specified before the data were reviewed. Risk groups were defined with the use
of Gleason scores from the pathological review
as follows: low risk, PSA level less than 10 and
either a Gleason score of less than 7 or WHO
grade 1 (on a scale of 1 to 3, with higher grades
indicating more aggressive disease) in tumors
that were diagnosed only by means of cytologic
assessment; high risk, PSA level of 20 or higher
or a Gleason score greater than 7; and inter
mediate risk, all patients who did not fulfill the
criteria for low or high risk. The modification of
the effect of radical prostatectomy was tested in
the Cox proportional-hazards model by including an interaction term between the subgroup
category and randomization group.
The prevalence of the use of palliative treatment
was calculated at every other year of follow-up,
ending at 18 years after randomization. Palliative treatment was androgen-deprivation treatment
(antiandrogen therapy or gonadotropin-releasing
hormone analogues or orchiectomy) in patients
with or without verified metastases and in patients with metastases who had received other
palliative treatment (external or internal palliative radiation therapy, laminectomy, or chemotherapy drugs).
R e sult s
A total of 347 men were randomly assigned to
the radical-prostatectomy group, and 348 men
were assigned to the watchful-waiting group.
The baseline characteristics of the two groups
were similar; the mean age of the men in both
groups was 65 years. Only 12% of the patients
had nonpalpable T1c tumors at the time of enrollment in the study. The mean PSA level was
approximately 13 ng per milliliter (Table S1 in
the Supplementary Appendix, available with the
full text of this article at NEJM.org). By December 31, 2012, a total of 294 men in the radicalprostatectomy group had undergone a radical prostatectomy, and 294 men in the watchful-waiting
group had not received curative treatment. In the
radical-prostatectomy group, 23 patients (16 pa-
Probability
No. at Risk
Probability
No. at Risk
Probability
No. at Risk
No. at Risk
Probability
347
18
154
145
Years
136
185
166
Years
135
115
110
Years
99
236
168
87
No. at Risk
12
15
18
144
132
Years
114
124
96
60
No. at Risk
12
15
18
81
80
69
Years
58
12
15
18
348
1.0
0.8
0.6
0.4
0.2
0.0
334
306
251
211
143
61
12
15
18
102
75
34
12
15
18
109
68
27
12
15
18
95
66
31
12
15
18
75
55
18
12
15
18
41
22
12
Age <65 Yr
166
1.0
0.8
0.6
0.4
0.2
0.0
157
144
118
Age 65 Yr
Years
112
72
27
No. at Risk
12
15
18
182
1.0
0.8
0.6
0.4
0.2
0.0
177
162
133
Low Risk
Years
89
72
40
No. at Risk
12
15
18
131
1.0
0.8
0.6
0.4
0.2
0.0
128
122
109
Intermediate Risk
Years
100
68
33
No. at Risk
High Risk
All Patients
Years
Intermediate Risk
1.0
0.8
0.6
0.4
0.2
0.0
Years
Low Risk
148
1.0
0.8
0.6
0.4
0.2
0.0
15
Probability
0
118
1.0
0.8
0.6
0.4
0.2
0.0
271
12
Age 65 Yr
190
1.0
0.8
0.6
0.4
0.2
0.0
311
Years
Age <65 Yr
157
1.0
0.8
0.6
0.4
0.2
0.0
339
Probability
1.0
0.8
0.6
0.4
0.2
0.0
Probability
Probability
No. at Risk
B Watchful Waiting
All Patients
Probability
Probability
No. at Risk
1.0
0.8
0.6
0.4
0.2
0.0
Probability
Probability
A Radical Prostatectomy
12
15
18
133
1.0
0.8
0.6
0.4
0.2
0.0
126
113
91
High Risk
Years
47
28
14
No. at Risk
84
80
71
51
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The
n e w e ng l a n d j o u r na l
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Table 1. Cumulative Incidence, Absolute Risk Reduction, and Relative Risk of Death from Any Cause, Death from Prostate Cancer,
and Development of Distant Metastases at 18 Years of Follow-up.*
End Point
Absolute Risk
Reduction with
Radical
Prostatectomy
Cumulative Incidence
Radical Prostatectomy
(N=347)
Relative Risk
with Radical
Prostatectomy
(95% CI)
P Value
Watchful Waiting
(N=348)
no. of
events
% (95% CI)
no. of
events
% (95% CI)
percentage
points (95% CI)
200
247
<65 yr
69
112
65 yr
131
135
Low
51
85
Intermediate
87
95
High
62
67
63
99
<65 yr
31
58
65 yr
32
41
Low
11
20
Intermediate
24
50
High
28
29
89
138
<0.001
<65 yr
45
76
<0.001
65 yr
44
62
0.04
<0.001
<0.001
0.52
0.002
0.02
0.34
0.001
Age
Tumor risk
0.002
0.19
0.17
<0.001
Tumor risk
0.84
Distant metastases
All
Age
8.9 (0.5 to 18.3)
Tumor risk
Low
15
35
0.006
Intermediate
37
59
<0.001
High
37
44
145
235
<0.001
<65 yr
68
122
<0.001
65 yr
77
113
<0.001
Low
32
63
0.001
Intermediate
65
98
<0.001
High
48
74
<0.001
0.39
Androgen-deprivation
therapy
All
Age
Tumor risk
936
67
1
0
95
85
0
0
135
112
1
1
247
15
27
46
55
33
88
5
1
6
8
4
12
9
11
8
20
8
28
29
8
6
5
11
8
19
45
50
20
65
94
41
58
99
54
62
* All events were evaluated by the dependent end-point committee.
1
0
87
51
0
1
131
69
0
1
200
Any cause
23
48
36
75
32
107
With no evidence of metastases or local
progression or recurrence
1
3
1
4
5
With unknown status regarding metastasis
but with local progression
3
9
2
12
14
Without metastases but with local
progression or recurrence
6
3
1
7
3
10
With metastases
34
63
24
11
40
99
32
31
63
137
Other cause
38
28
number
148
Intermediate
Risk
Low
Risk
All Men
High
Risk
Intermediate
Risk
Low
Risk
Age
65 yr
Age
<65 yr
All Men
Prostate cancer
Cause of Death
Distant Metastases
Table 2. Cause of Death According to Study Group, Age at Diagnosis, and Tumor Risk.*
Age
<65 yr
Mortality
Age
65 yr
High
Risk
38
937
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Bone metastases
Metastases to sites
other than bone
Cumulative incidence of metastases
Probability
No. at Risk
Probability
No. at Risk
Probability
No. at Risk
No. at Risk
Probability
347
18
154
145
Years
136
185
166
Years
135
115
110
Years
99
236
168
87
No. at Risk
12
15
18
144
132
Years
114
124
96
60
No. at Risk
12
15
18
81
80
69
Years
58
12
15
18
348
1.0
0.8
0.6
0.4
0.2
0.0
334
306
251
211
143
61
12
15
18
102
75
34
12
15
18
109
68
27
12
15
18
95
66
31
12
15
18
75
55
18
12
15
18
41
22
12
Age <65 Yr
166
1.0
0.8
0.6
0.4
0.2
0.0
157
144
118
Age 65 Yr
Years
112
72
27
No. at Risk
12
15
18
182
1.0
0.8
0.6
0.4
0.2
0.0
177
162
133
Low Risk
Years
89
72
40
No. at Risk
12
15
18
131
1.0
0.8
0.6
0.4
0.2
0.0
128
122
109
Intermediate Risk
Years
100
68
33
No. at Risk
High Risk
All Patients
Years
Intermediate Risk
1.0
0.8
0.6
0.4
0.2
0.0
Years
Low Risk
148
1.0
0.8
0.6
0.4
0.2
0.0
15
Probability
0
118
1.0
0.8
0.6
0.4
0.2
0.0
271
12
Age 65 Yr
190
1.0
0.8
0.6
0.4
0.2
0.0
311
Years
Age <65 Yr
157
1.0
0.8
0.6
0.4
0.2
0.0
339
Probability
1.0
0.8
0.6
0.4
0.2
0.0
Probability
Probability
No. at Risk
B Watchful Waiting
All Patients
Probability
Probability
No. at Risk
1.0
0.8
0.6
0.4
0.2
0.0
Probability
Probability
A Radical Prostatectomy
Metastases detected
at death
12
15
18
133
1.0
0.8
0.6
0.4
0.2
0.0
126
113
91
High Risk
Years
47
28
14
No. at Risk
84
80
71
51
939
The
No androgen-deprivation
therapy or metastases
Androgen-deprivation
therapy with antiandrogen
therapy, no metastases
n e w e ng l a n d j o u r na l
Androgen-deprivation
therapy with GnRH or
orchiectomy, no metastases
A Radical Prostatectomy
Androgen-deprivation
therapy with confirmed
metastases
Androgen-deprivation therapy
and other palliative treatments
(cytotoxic drugs or laminectomy)
with confirmed metastases
All Patients
1.0
Proportion
of Survivors
Proportion
of Survivors
m e dic i n e
B Watchful Waiting
All Patients
1.0
0.8
0.6
0.4
0.2
0.0
of
0.8
0.6
0.4
0.2
10
12
14
16
0.0
18
Years
No. at Risk
343
332
311
257
236
201
145
87
No. at Risk
Age <65 Yr
0.8
0.6
0.4
326
306
270
156
151
145
10
12
14
16
138
132
124
111
89
60
238
173
111
14
16
61
0.6
0.4
No. at Risk
161
153
144
10
12
18
0.6
0.4
0.2
127
113
102
90
60
34
Age 65 Yr
1.0
Proportion
of Survivors
Proportion
of Survivors
211
18
Years
0.8
0.8
0.6
0.4
0.2
187
181
166
147
10
12
14
16
0.0
18
180
173
162
143
Years
No. at Risk
16
0.8
0.0
18
Age 65 Yr
1.0
0.0
14
Age <65 Yr
Years
No. at Risk
12
0.2
0.2
0.0
341
1.0
Proportion
of Survivors
1.0
Proportion
of Survivors
285
10
Years
125
10
12
14
16
18
Years
112
90
56
27
No. at Risk
125
109
83
51
27
Figure 3. Prevalence of Metastases and Use of Palliative Treatment in Men Alive at Various Time Points since Randomization.
The use of gonadotropin-releasing hormone (GnRH) analogues is considered to be medical castration, and orchiectomy is considered
tobe surgical castration.
940
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