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The Prostate 29:249-260 (I 996)
Prostate Cancer and Smoking: A Review of
Case-Control and Cohort Studies
L.H. Lumey
Division of Epidemiology, American Health Foundation, New York
BACKGROUND. The purpose of this study was to undertake a systematic analysis of the
relation between smoking and prostate cancer.
METHODS. All published case-control and cohort studies including relevant data on this
topic were collected. The magnitude of potential sources of divergent results among casecontrol studies was estimated comparing current, former, and ever to never smokers, stratified by type of controls (hospital vs. population) and by race. Cohort studies were discussed
individually.
RESULTS. Neither a clinically nor a statistically sigruficant association between smoking
and prostate cancer seems likely, but it cannot be ruled out entirely. The association between
other purported risk factors and prostate cancer is not likely to be confounded by the
incomplete measurement and control for smoking habits because smoking and prostate
cancer are not related.
CONCLUSIONS. For a valid assessment of other risk factors in prostate cancer patients the
collection of complete smoking information is therefore less critical than in patients with
other diseases. For a definitive assessment of the effect of smoking on prostate cancer
incidence and mortality however, future studies need to focus on the collection of information on lifetime smoking habits, including tar exposure. 0 1996 Wiley-Liss, Inc.
KEY WORDS:
prostate cancer risk factors, cigarette smoking, dose response, cumulative tar exposure
INTRODUCTION
After lung cancer, prostate cancer is the second
leading cause of cancer deaths in black and white
men in the United States. In addition, the incidence
and mortality of prostate cancer are increasing, with
an estimated number of 244,000 newly diagnosed
cases and over 40,000 deaths in 1995 [l]. Therefore,
full attention needs to be given to the etiology and
prevention of this type of cancer.
The rates for clinically overt prostate cancer increase with age, a family history of the disease, and
with living in Western and more developed countries. They are much higher in black compared to
white men, and black men in the United States have
the highest rates in the world [2-51. Incidence and
mortality are low in Asia, but rise sigruficantly among
immigrants to Western countries [6]. The low rates in
Asia compared to Northern Europe and the United
States and the findings from immigrant studies suggest that environmental factors, especially differences
0 1996 Wiley-Liss, Inc.
in dietary fat intake, could be an important determinant of prostate cancer disease. Indeed, most retrospective [7-141 and prospective [15-19] epidemiologic
studies on dietary factors show a modest (30-5070)
increase in risk for subjects with a high, compared to
a low level of dietary fat intake. However, differences
in fat intake between ethnic groups can explain only
part of the differences in prostate cancer [20].
The reported increase in risk could be an underestimation because of the intrinsic difficulties of dietary
assessment of past andor present fat intake [21], and
of the narrow range of fat intake [22] in the societies
where these studies were carried out. On the other
Received for publication January 26, 1996; accepted January 30,
1996.
Address reprint requests to L.H. Lumey, American Health Foundation, Division of Epidemiology, 320 East 43rd Street, New York,
NY 10017.
~~~
TABLE 1. Case-Control Studies: Prostate Cancer Prevalence and Smoking
setting
1. Selected hospitals
nationwide,
American Health
Foundation, New
York City,
1%9-1984
2. Cancer registries,
Atlanta, Detroit,
New Jersey,
1986-1989
3. Local hospitals,
Montreal, Canada,
1979-1985
4. Cancer registry,
Alberta, Canada,
1981-1963
Reference
Yu et al.,
1988 [28]
Hayes et
al.. 1994
1291
Cases"
Controls'
W: 989
B161
W 2,791
B 320
Hospital
w
Matching
variables
(stratum
sizein
years)
Ever
smokers
among
cased
controls
OR (95% CI)b
(W)"
Current
smokers
Former
smokersc
Age(5)
Hospital
Race
Interview
date(1)
W 76/78
B 80/82
1.0 (A-1.2)
0.7 (.4-1.3)
.9 (.7-1.1)
1.4 (.7-2.7)
1.2 (.a-1.7)
1.0 (.7-1.4)
1.2 (.9-1.6)
1.1 (.7-1.5)
W: 502
B: 479
721
B:594
Population
Age(5)
Race
Region
W: 81/77
Siemiatycki
et al., 1995
[MI
449
1,266
Hospital
Age
87/80
Fincham et
382
625
Population
Age
m 6
.87 (.61-1.24)
362
358
685
679
Population
Age51
57/58
1.28 (.76-2.17)
(over 28.6
pack-years)
al., 1990
B80/78
Comments
No relation with amount
(pack-years or CPD) or
duration of smoking.
No relation with amount
smoked. Also 533
population controls,
presumably not
included for OR
estimates.
.63 (.61-1.13)
No relation with amount
(CPD) of smoking. No
difference in risk
between current and
former smokers. Mixed
ethniaty of mainly
European origin.
Relation with duration of
smoking (pack-years)
in aggressive tumors
.99 (.76-1.29)
only.
1.0 (.7-1.5)
I311
5. Cancer registry and Slattery and
pathology labs,
West, 1993
Utah,1984-1985
(321
Elghany et
al., 1990
Ever
smokersC
W1
6. Cancer registries,
The Netherlands,
1988-1990
Van Der
Gulden et
al., 1994
1341
345
1346
Hospital
WH)
No matching,
Cases 3 years
older than
controls.
95/90
7. Regional hospitals,
Northern Italy,
1985-1991
Tavani et
al., 1994
1351
Talamini et
al., 1993
1361
281
599
76/78
271
685
Hospital
Matching for
hospital only.
Cases 7 years
older than
controls.
8. Cancer registry,
L.A. County,
1979-1982
Honda et
a]., 1988
1371
216
216
Population
Age
Neighborhood
80/68
9. Local hospitals,
American Health
Foundation, New
York City,
1965-1967
Wynder et
al., 1971
[38]
217
200
Hospital
No matching.
Age of cases
and
controls not
stated.
82/80
2.12 (1.2-3.62) No relation with amount
(CPD), duration, or
age started smoking.
No difference in risk
between current
smokers and those
who quit >25 years
ago. In summary, "no
causal relation."
.78 (54-1.15) .81 (.55-1.20)
.91 (.61-1.35)
.92 (3-1.58)
.76 (.51-1.13)
No relation with amount
(CPD) or duration of
smoking. No relation
with age started
smoking.
1.9 (1.2-3.0) Vasectomy series: only
men under 60 years of
age. Retrospective case
ascertainment (19% of
cases had died).
Positive association
with duration of
smoking. 55% of
eligible cases were
never interviewed.
No relation with amount
(CPD) of smoking. OR
not adjusted for age.
(Continued)
Prostate Cancer and Smoking
251
TABLE 1. (Continued) Case-Control Studies: Prostate Cancer Prevalence and Smoking
setting
10. Retirement
community and
tumor registry,
L.A. County,
1972-1982
Reference
Ross et al.,
1987 (121
Ross et al.,
1983 [39]
11. Local hospital,
Tokyo, Japan,
1963-1978
Niijima and
Koiso, 1980
1401
Cases"
w
142
B 142
w
110
187
Controls'
w
No matching.
cases of
"almost
identical" age
compared to
controls.
55/55?
139
139
Hospital
Age.
interviewer
117
186
(BPH)
110
Hospital
Age, hospital,
admission date
Hospital
15. M.D.Anderson
cancer Center,
Houston, Texas,
1985-1987
16. Selected hospitals,
Japan, 1976
Newell et
al., 1989
1441
110
220
Hospital
Age(1)
Date of
diagnosis
M i s h i ~et
al., 1985
1451
100
Population
100
18. Localhospitals,
Minneapolis, St.
Paul, 1976
Schumanet
al., 1977
147l
40
w
47
B17
Hospital
(BPH)
35
Population
43
Hospital
Current
smokers
Former
smokers'
60163
?
269
Hospital
B:l8
w
Age(l)t
race
176
W: 22
(%)a
w: 110
Population
12. Roswell Park
Kolonel
Memorial
and
Institute, Buffalo, Winkelstein,
1977 141)
New York,
1957-1964
13. h l h o s p i t a l s ,
Schwartzet
Paris, France,
al., 1%1
[42]
1954-onward
Oishi et al.,
14. Local hospitals,
Kyoto, Japan,
1989 1431
1981-1984
Checkoway
et al., 1987
(461
controls
Age(%
race
Age(%
race
200
OR (95% Cl)b
cased
142
B 142
Hospital
17. Local hospital,
Chapel W, NC,
1984-1985
Ever
smokers
among
Matching
variables
(stratum
s u e in
Yeam)
B 48/48
Ever
smokers'
Comments
.9
1.1
No relation with amount
(CPD) of smoking.
.9 (31
discordant
pairs)
"No great difference" in
smoking between
cases and controls.
1.1 (Non
ca
Controls)
1.0 (ca
Controls)
No relation with
smoking.
79/73
No relation with
smoking habits.
Current compared to
noncurrent, former
compared to
nonformer smokers.
Inverse relation with
smoking.
1.36 (.76-2.45) .77 (44-1.35)
.59 (A-1.03) 1.41 (.81-2.48)
1318 = 1.63
(matched
pairs
design)
No matching.
Age of cases
and
controls not
stated.
Age(3). race,
admission date
83/87
83/64
(POP)
83/87
(Hasp)
1.71 (33-5.2) Black and white men
combined.
2.79 (.%-9.29)
(Population
controls)
.76 (.20-2.88)
(Hospital
controls)
"W, white men; B, black men.
bAdjusted for age at diagnosis unless otherwise indicated.
Wsk categories vs. never cigarette smokers unless otherwise indicated.
hand, it could be an overestimation resulting from
inadequate control for smoking in the event that
smoking and prostate cancer are related. Because
high fat intake and smoking are highly correlated
themselves [23], the latter association could spuri-
ously inflate the association with prostate cancer and
dietary fat.
Whereas some reviews conclude that there is no
association between smoking and prostate cancer
[2-4,241, an analysis specifically focusing on this re-
252
Lumey
lation reported a positive association [25], as have
some case-control and cohort studies. There is a
need, therefore, to undertake a systematic analysis of
published reports on the relation between smoking
and prostate cancer to clanfy this issue. The magnitude of the effect needs to be estimated, and a reasoned assessment as to whether an association
should be regarded as causal needs to be made. In
addition, several unresolved issues emerging from
the present studies need to be identified and resolved. These concern conflicting findings emerging
from retrospective (case-control) vs. prospective (cohort) studies, and from case-cohort studies with different (hospital vs. population) types of controls. The
effects of publication bias, possibly favoring reports
of positive as opposed to negative findings, and the
effect of the choice of study populations (white vs.
black men) also require quantification. Such a systematic analysis is presented hereunder.
MATERIALS AND METHODS
Study Materials
From previous reviews [2-4,251 and from a Medline search from 1966 onward, we collected all publications which included data on the association between smoking and prostate cancer, regardless of
primary study aim. These studies were arranged by
study size (number of prostate cancer cases or
deaths), separately for case-control and cohort studies. The latter include studies of incidence and of
mortality. For case-control studies we listed the setting, the study reference, the number and type of
cases and controls (hospital vs. population), the
matching criteria for the controls (age, race, hospital),
the proportion of ever smokers among cases and controls, and the estimated odds ratio (OR) for various
categories of smokers (current, former, ever) vs.
never smokers of cigarettes. In addition, we listed
relevant comments, especially on the observed relations between duration and amount of smoking with
prostate cancer (Table I).
For cohort studies we listed the setting, the period
when the cohort was assembled, cohort size, the
number of incident cases or prostate cancer deaths,
the follow-up period, the proportion of current smokers among the deaths or cases, the relative risk of
prostate cancer mortality (or incidence) by level of
smoking, and we compared former vs. never smokers. We also listed comments on the relation between
duration and amount of smoking with prostate cancer (Tables I1 and 111).
One relatively small case-control study (included
in Table I as reference 43) was not further analyzed
because it did not report on the risk of current,
former, or ex-smokers relative to never smokers, but
instead contrasted current with noncurrent, and
former with nonformer smokers.
Analytic Methods
For case-control studies we plotted the ORs (age
adjusted if provided, otherwise not adjusted as calculated from tabular data) for current, former, and
ever smokers, by effective example size, in so-called
funnel plots [26]. This is a powerful graphical technique to assess the presence of publication bias (i.e.,
a relative absence of negative findings among the
smaller published studies).
Effective sample size (ESS) takes the different caseto-control matching ratio between studies into account and denotes the number of cases that would be
required for equivalent study power if only one control per case were to be used. It is well known that
multiple controls per case can significantly increase
study power and hence some form of standardization
of study size is required for a) a comparison of studies
by size and for b) the optimal weighing of studies in
statistical procedures. ESS was calculated inverting
the sample size formula for multiple controls per case
as given by Schlesselman [271. As an example, the
ESS for the Yu et al. [28] case-control study among
989 white cases and 2,791 white controls would be
1,460, because a study with 1,460 cases and 1,460
controls has the same statistical power to detect a
difference in risk factors between cases and controls.
We then estimated the magnitude of two potential
sources of divergent results among the published
case-control studies, namely race (black vs. white
men), and the choice of controls (hospital vs. population). Using published tabular data as available, the
Mantel-Haenszel summary OR across studies within
these categories, comparing current, former, and
ever to never smokers, was then calculated. Tabular
data were generally not available from smaller studies
(ESS less than 200).
For cohort studies, it was not possible to calculate
a weighted average of the relative risk across studies
for lack of data on follow-up time. Therefore, cohort
studies will be discussed individually.
RESULTS
Case-Control Studies
We identified 18 studies [28-471 from the literature, with a study size ranging from 40 to over 1,000
cases, as in the study camed out by Yu et al. (28) from
the American Health Foundation (Table I). Duplicate
reporting had occurred for several studies. Black men
Prostate Cancer and Smokinn
253
TABLE II. Cohort Studies: Prostate Cancer Mortality and Smoking
Current
Cohort
size
prostate
cancer
deaths
FollowUP
(years)
293,916
4.607
2
%?E
[@I
3,124
Rogot and
Murra
1980 [&I
1,020
Kahn, 1966
582
Assembled
Reference
1. US.
1954-1957
veterans,
1917-1940
Hsin et al
1991 748481 .'
Setting
sdeaths
gt:F
Relative risk (95% CI) by smoking level'
2
(96)
1
26
31
1.11
.97-1.27
(260)
26
?
1.0
1.1
826
16
?
1.22
1.46
568
40
18b
.79
1.07
1.24
196
20
.R
.80
.97
69
10
6Zb
319
3-5
63
3
1.15
1.23
1.05-1.27 1.09-1.38
(695)
(374)
1.2
[511
52
2. Multiple 1972-1976
Risk
Factor
Intervention
Cou
al. 1 % ;
348J374
Dollet al.,
1994 I541
34,440
4
Former
smokers
Comments
1.51
1.13 > 99% Whites
1.20-1.90 1.03-1.24 Level 1: 1-9
(78)
(817) Level2 10-20
Level 3 21-39
1.6
Level 4 40+ CPD
Smoking level as per
status at study entry
(1954-1957).
No relation to age started
smoking. Positive
assodahon with number
of years smoked
cigarettes. Cigarette
smokers who also took
pi dcigadsmokeless
, , ; go t
excluded from
McLaughlin report.
Relative risk for current
smokers/( e m of
follow-up; 2.17/(2.5),
1.7/(8.5),1.31/(16),
1.18/(26).
93% white smokers
Level 1
MRFlT initial screening
Trial
(MWTT)
3. British
doctors
1951
Doll and
Peto, 1976
I551
Doll and
w, 1966
1561
Hammond,
1966 [57l
L
4. American 1959-1964
Cancer
z2
Level 1: 1-14
Level 2 15-24
Level 3 25t CPD
Smoking levels as per
status at follow-u No
trend in smoking!evels.
RR for current smokers:
.99 (1994).
1.10
1
440.558
Level 1:Ever smokers
1.01
(131)
25 states
124
Hammond,
1964 [581
<3
71
52
134
5. Sweden,
1963
census
sample
6. Hawaii,
196-1964
Japanese
men
7. Minnesota, 1966
Lutheran
Brotherhood
Cohort
Carstensen
25,129
et al., 1987
I591
Seversonet
7,999
al., 1969 [l;l
193
4-19
37
174
18-21
37
Hsin et al.,
1990 7161
149
20
61
8. U.S.
college
alumni,
entered
School
1916-1950
9. ]a an
sel)ect;.d
health
center
Whittemore
et al., 1985
47,271
107
16-50
Hirfama
1974 [iej
122,261
63
10
Weirand
Dunn, 1970
[611
68,153
37
5-8
1%2
17,633
.97
(88)
1.11
(69)
1.1
(26)
Age 40-69
Age 70-89
0.8
(31)
0.9
(15)
Level 1: 1-7
Level 2: 8-15
Level 3 16+ CPD
Level 1: Current smokers
1.7
.8-3.5
1.4
.4-4.4
(3)
Level 1: 1-19
Level 2 20-29
Level 3:30+ CPD
No dear dose response.
23% of subjects lost to
follow-up.
RR of ever smokers: 1.8
(1.1-2.9)
No association
Nested case control study
.87
(6)
1.6
.8-3.5
(12)
(11)
[W
1965
.95
.61
Level 1: Current smokers
diShiCtS
10. California, 1954-1957
union
members
.78
(37)
Level 1: Ever smokers (aU
forms of tobacco)
"Number of deaths in brackets.
bAmong entire cohort.
were included in only 4 of these 18 studies [12,28,29,
461. There was a fair mix of hospital and population
controls, and matching of cases with multiple controls (generally three or less) was common. In only
two studies [34,46]were patients with benign prostate hypertrophy (BPH) used as controls. Matching
variables typically included age (within 1-5 years),
race, and date of diagnosis or a proxy thereof. The
254
Lumev
TABLE 111. Cohort Studies: Prostate Cancer Incidence and Smoking
Current
smokers
Cohort
Setting
Assembled
1969
1. Third U.S.
National
Cancer
SWeY
2. Kaispr
1978-1985
Permanente,
Northern
CA
1976
3. Seventh
Reference
Relative risk (95% CI) by
smoking level'
Follow-
among
UD
deaths
(46)
1
2
3
.!a
deaths
(years)
7,518
257
Cross
section
?
.74
.74
Hiatt et al.,
1% 1631
43,432
238
4.6
27
1 .o
.6-1.6
(24)
1.9
1.2-3.1
(2.5)
Millset al.,
1989 [I51
14,000
180
6
?
.49
(3)
Williams and
Horn, 1977
size
Pr'r.",:'
Former
smokers
Comments
Level 1: < 20
Level 2: 21-39
Level 3 40+ CPD
[621
FLentists.
1.1
.8-1.5
(94)
23%blackmen
Level 1: C = 20 CF'D
Level 2: > 20 CPD
1.24
,914.67
(79)
Level 1: current smokers
(1989 study)
Level 1: 1-14
CA
Level 2: 15+ CPD (1992
study, relates to
ex-smokers only)
Nonsienificant trend for
amous and duration of
smoking. Also,
nonsi Scant relation
(OR E 4 ) with duration
(GE 10 years) of smoking.
No association
Mills and
Beeson, 1992
[MI
4.
us.
college
alumni,
entered
school
1916-1950
5. Retirement
community
and tumoi
1%2
Whittemore
et al., 1984
47,271
243
(includes
107 deaths)
16-50
?
Ross et al.,
5,106
138
3-7
41
161
1981-1985
.9
.7
Level 1: 1-10
Level 2: 11-20
Level 3 21+ CPD
.7
1990 1-56]
5%County
"Numberof cases in parentheses.
proportion of ever smokers among the cases ranged
from 48 to 95%.
A funnel plot [26] of the ORs for ever smokers vs.
never smokers by ESS shows that smaller studies
generally report a positive association between smoking and prostate cancer. For larger studies, except the
study carried out by van der Gulden et al. [MI, there
is no such pattern (Fig. 1). This indicates that negative studies showing no association between prostate
cancer and ever smoking are underrepresented in the
published reports. Funnel plots for current and
former vs. never smokers show a similar pattern. The
weighted average across studies of the ORs for current (OR: .97), former (OR: .%), and ever (OR: 1.04)
vs. never smokers stratified for type of control (hospital vs. population) and race suggests there is no
association between smoking and prostate cancer
(Table IV). However, studies with hospital controls
tend to show a weak inverse, and studies with population controls a weak positive association for current and former compared to never smokers. The
ORs are close to unity and statistically nonsignificant
for both types of study. These patterns hold in both
black and white men.
Studies with hospital and population controls also
differed with respect to the smoking habits of cases
and controls. Compared to population controls, hospital controls were more likely to be current (40 vs.
!
I]u7
-
!
a
0
1
r
.I
'
0
W
loo0
1W
Effective Sample She (Caws)
Fig. 1. Smoking and prostate cancer. ORs for ever w. never
smokers by ESS. Individual studies are numbered as in the reference
list. Studies 12.28, and 29 have separate entries for black and white
men. Study 47 has separate entries for hospital and population
controls.
37%) or ever (80 vs. 71%) smokers, and less likely to
be former (36% vs. 46%) smokers. An unexpected
finding was that these patterns also hold for the cases
in both groups of study. Smoking is more common in
black compared to white men (Table V).
Cohort Studies
We identified 10 studies [16-18, 48-61] with a
prostate cancer mortality follow-up from the litera-
Prostate Cancer and Smoking
255
TABLE IV. Case-Control Studies, Summary ORs (95% CI) for Current, Former, and Ever
Compared to Never Smokers by Type of Controls by Race*
Current
Former
Ever
OR
CIS
OR
CIS
OR
CIS
.94
1.04
.98
(.80-1.10)
(37-1.25)
(.87-1.11)
.88
1.05
.94
(.74-1.04)
1.01
1.09
1.04
(.89-1.15)
(.94-1.26)
( .98-1.15)
.71
.76
.87
(.41-1.21)
(.67-1.37)
(.65-1.17)
1.36
1.25
1.28
(.74-2.49)
(.88-1.79)
(.94-1.73)
.87
1.10
1.03
(.80-1.52)
(. 78-1.35)
.91
1.03
.97
.78-1.07
.87-1.21
.81-1.08
.91
1.10
.99
.77-1.07
.91-1.33
.87-1.12
1.00
1.09
1.04
.88-1.14
.95-1.24
.95-1.14
~
Whites
Hospital controls
Population controls
All
Blacks
Hospital controls
Population controls
All
Combined
Hospital controls
Population controls
All
(.&4-1.31)
( .82-1.08)
(.52-1.45)
95% CI and Summary ORs determinedby the Mantel-Haenszel method. Whites: Five studieswith hospital
and six with population controls. Blacks: One study with hospital and one study with population controls.
TABLE V. Case-Control Studies Percentage of Smokers
(Current, Former, and Ever) for Cases and Controls
(Hospital and Population) by Race*
Smokers
Controls
Whites
Hospital
Population
Blacks
Hospital
Population
Combined
Hospital
Population
Cases
Whites
Hospital
Population
Blacks
Hospital
Population
Combined
Hospital
Population
Current
Former
Ever
37
36
39
50
80
70
61
41
21
37
82
78
40
37
36
46
80
71
38
35
38
52
82
71
48
37
32
80
43
80
40
37
49
82
73
35
*Studiesweighed by ESS.Whites: six studies with population and
six studies with hospital controls. Blacks: one study with population and one study with hospital controls.
ture (Table 11)and 5 studies [15,62-661 with a prostate
cancer incidence or prevalence follow-up (Table 111).
The best known mortality studies include the U.S.
Veterans study assembled between 1954 and 1967
[48-521, the British physicians study assembled in
1951 [54-561, and the American Cancer Society volunteer study assembled between 1959 and 1960
[57,58]. We also identified a report on prostate cancer
deaths and smoking among men screened between
1972 and 1976 for the MRFIT cardiovascular disease
risk factor intervention trial [53].
The number of prostate cancer deaths ranges from
37 in a Californian Union Members study [61] to 4,607
in the U.S. Veterans study [48], and the number of
new cases ranged from about 130 to 250. As best we
know no significant number of black men was studied except in the Kaiser Permanente morbidity follow-up, which included 23% black men among 238
new cases [63]. In this study results were not broken
down by race, however.
In several studies a repeated outcome assessment
took place. Among the U.S. Veterans [48-521, prostate cancer mortality was assessed after 2 1/2, 8 1/2,
16, and 26 years of follow-up (when 66% of the original cohort was no longer alive), and among the British physicians [54-561 mortality was assessed at 10,
20, and 40 years of follow-up (when 60% of the original cohort was no longer alive). In both studies mortality follow-up was virtually complete. In nearly all
cohort studies, excepting the British doctors, study
subjects were not contacted at regular intervals, however: subjects’ vital status and cause of death (if applicable) were once ascertained through independent
data sources such as insurance records. Therefore,
prostate cancer mortality in all studies except the British physicians’ study was related to the subjects’
256
Lumev
smoking status at study entry. Generally, smoking
status was compared for one to four levels of amount
of cigarettes smoked per day (CPD) relative to never
smokers, and for former smokers compared to never
smokers.
Seven of 10 cohort studies showed no association
with amount of smoking (CPD) and prostate cancer
mortality. Only the U.S. Veterans study [48], the
h4RFIT screening cohort [53], and the Lutheran
Brotherhood cohort [16] reported a positive association. As mentioned before, smoking habits at study
entry in these three studies were related to cause of
death after an extended follow-up period ranging
from 16 to 26 years. The risk of prostate cancer mortality in the U.S.Veterans study is marginally elevated with a risk ratio (RR) of 1.18 (1.09-1.28) for
current smokers and 1.13 (1.03-1.24) for former
smokers. In the MRFIT study the reported RR was 1.3
(1.1-1.5) for the risk of current vs. nonsmokers. In
the Lutheran Brotherhood cohort the RR was 1.9
(1.1-3.3) for former and 1.8 (1.1-2.5) for ever smokers.
In the U.S.Veterans study there is a steady decrease in the relative risk of former vs. never smokers
with increasing follow-up time. For current smokers
the RR declined from 2.17 after 2 1/2 years of follow-up to 1.18 after 26 years of follow-up [48]. Except
for men smoking one pack a day or more in the Kaiser
Permanente follow-up study [63], with a RR of 1.9
(1.2-3.1) compared to never smokers, no (or negative) associations between smoking and newly diagnosed prostate cancer cases were reported.
DISCUSSION
From our review of published case-control and cohort studies relating smoking habits to prostate cancer mortality and prevalence, a number of conclusions can be drawn. Because so few studies include
black men, our conclusions refer to white men unless
otherwise indicated.
Published case-control studies show that the association between smoking (current, former, or ever)
and prostate cancer is very weak, if at all present. The
absence of any association holds in spite of a bias
favoring the publication of positive studies. In addition, reports including elevated ORs are usually atypical in one or more respects. As an example, controls
for the Dutch cancer registry study (OR = 2.12 for
ever smokers) [34] were selected from patients with
BPH. Since there is evidence that BPH is negatively
associated with smoking [25], this choice of controls
might well overestimate a smoking-prostate cancer
association. The odds for ever smoking are also evaluated (OR = 1.71) in the second study with BPH
controls [46].The positive Dutch study also had the
largest proportion of ever smokers among cases
(95%)and controls (90%)of all reported studies, and
this tends to inflate the OR as nearly all cases and
controls are smokers. For these and other reasons the
authors of the Dutch study do not interpret the reported positive association as causal.
The other study with a reported increased risk (OR
= 1.9 for ever smokers) is atypical in that only men
under age 60 were included since originally the study
was designed to evaluate the relation between vasectomy and prostate cancer [37]. This also explains why
cases (of which 19% had died) were ascertained retrospectively, which could be a source of bias of unknown direction and magnitude.
Contrary to other suggestions [48,63] we found
that case-control studies with population controls are
quite common. We documented 11 studies with hospital and 7 studies with population controls. In addition, we have no evidence that the positive results
from case-control studies were exclusively due to the
use of hospital controls. Whereas the prevalence of
smoking is larger among controls in case-control
studies with hospital controls, which has been observed previously [25,48,63,67], the apparent decrease in OR for prostate cancer for smokers combining all studies with population controls is only
marginal (OR = .91 for current smokers and .91 for
former smokers) because the proportion of smokers
among the cases in these studies is also higher.
Whereas variations in smoking rates among prostate
cancer cases in different hospitals can be expected
because of hospital-specific patient intake patterns, it
is unclear why smoking rates among cases should be
associated with the type of case-control study. The
only explanation, other than random variation, could
be that studies with hospital compared to studies
with population controls are carried out in hospitals
that have different patient characteristics. This requires further study. Whereas the use of population
controls results in slightly increased OR estimates for
current (OR = 1.03) and former (OR = 1.10) smokers, these results are still essentially indistinguishable
from unity both from a clinical and a statistical perspective. For the evaluation of the association between smoking and prostate cancer, the two types of
control both give a null result.
Finally, none of the case-control studies showed a
consistent relation between amount of smoking (pack
years or CPD), duration of smoking, age started
smoking, age quit smoking, or any other measure of
exposure with prostate cancer.
In summary, the absence of any relation between
smoking and prostate cancer in nearly all case-control
studies, and a plausible explanation for positive as-
Prostate Cancer and Smoking
sociations reported by the remainder, suggests that
the relation, if at all present, is unlikely to be causal in
white men. For black men the numbers studied are
(too) small, but there may be a suggestion of an elevated OR among former smokers. This could further
be explored.
In line with the findings from case-control studies,
most published cohort studies do not show a relation
between smoking and prostate cancer incidence or
mortality. There are three cohort studies that do report an association, and they need to be discussed in
some detail as they happen to be among the reports
with the largest number of cases. In all three studies
(U.S.Veterans [48], MRFIT [53], and Lutheran Brotherhood [16]), information on smoking status was only
collected at study entry. Mortality among the subjects
was then ascertained after a follow-up period ranging
from 16 to 26 years.
Because smoking status at study entry is used as a
proxy for smoking status at death, the study outcomes are likely to be biased for a number of reasons.
The first reason is that classification at study entry
does not take into account that, in the United States
and elsewhere, there has been a dramatic decline in
the proportion of smokers from 1950 to 1995. In the
U.S.Veterans study, comparing mortality in 1966 and
1982, the proportion of men who reported smoking at
study entry in 1954-1957 declined from 56% to 31%.
The authors of this study estimate that more than
40% of the smokers may have quit after study entry
[a].
In the British physicians study most doctors who
smoked in 1951 had ceased to do so in 1991 and the
prevalence of smoking between 1951 and 1991 declined from 62 to 18%.This could not be explained by
aging of the cohort [54]. (In the British study smoking
histories were taken at 10-year intervals and no association was seen between smoking and prostate cancer.) This decline in smoking prevalence over time
may also in part account for the apparent decrease in
relative risk of current and former smokers in the
U.S.Veterans study, from 2.17 (95% confidence interval [95% CI] not available) after 2 112 years of follow-up to 1.18 (1.09-1.38) after 26 years of follow-up
(Fig. 2) and for the decline in relative risk over time.
This could be expected if the excess risk of smoking
were additive and the background risk increases as
the cohort ages [68].
The second reason why a comparison of smokers
at study entry with subsequent mortality is likely to
be biased is that there has been a dramatic change in
the composition of the cigarettes smoked, from hightar, high-nicotine, nonfilter cigarettes smoked in the
1950s to low-tar, low-nicotine, filtered cigarettes
smoked at present (Fig. 2). It may well be that puff
size increased concomitantly, as it is inversely related
257
:I:
-
30.0 28.0 -
-
32.0
-
26.0
PL
16.0
-
14.0
-
18.0
12.0
10.0
t
2.3
2.1
P
:H
1.5
-
1.3
- 1.1
-
0.9
- 0.7
- 0.5
-
1950
25
- l3
22.0 241)
20.0
2.1
lD55
1900
1WS
1970
1975
1900
1o#I
a3
2OOO
AlldahcbnnbOnUSmulo(
Fig. 2. U.S. sales-weighted average tar and nicotine yields from
all domestic brands on the U.S. market, 1954-1993. Abbreviations:
RT, reconstituted tobacco; F, filter; ET, expanded tobacco. The
numbers 85, 100, and I20 in the figure denote cigarette length in
millimeters. (Figure reproduced, with permission. from Hoffmann
D, Hoffmann I: Tobacco consumption and lung cancer. In Hanten
HH (ed):“Advances in Basic and Clinical Research.” Boston: Kluwer Academic Publications, 1995, pp 1-42.)
to the average nicotine content of a cigarette [69,70].
The net effect of these changes with respect to the
cumulative tar exposure of smokers is hard to evaluate, but is likely to be associated with smoking level at
study entry. If so, a major source of bias would be
introduced. For the reasons given above, it is also
clear that cohort studies relating smoking status in
the remote past with prostate cancer mortality are not
very relevant for today’s smokers, even if they were
unbiased. An additional problem in cohort studies is
the loss to follow-up of the study subjects. Whereas
nearly all subjects were accounted for in the U.S.Veterans and the MRFlT follow-up studies, the Lutheran
Brotherhood study lost 23% of its subjects to followup. The authors report “no signhcant differences”
between subjects retained and subjects lost to follow-up but provide no further information [16]. It
would be of special interest to know the smoking
patterns at study entry, by follow-up status and
cause of death, to properly evaluate the results of this
study. Additional information on mortality among
those lost to follow-up could possibly be collected
from other sources, for instance the National Death
Index. This would indicate how loss to follow-up is
related to smoking status at study entry and cause of
death, which in turn permits an assessment of the
likelihood of bias.
Among cohort studies, current smokers are categorized in many different ways, using a variety of
cutpoints for CPD. This leaves too much opportunity
for ad hoc groupings after data inspection, and makes
comparisons between studies impossible. It is therefore difficult to critically evaluate the reported doseresponse relations of amount of cigarettes smoked
and prostate cancer mortality. For instance, in the
MRFIT screening cohort [53], prostate cancer deaths
are related only to two levels of smoking, smokers vs.
nonsmokers. In the Lutheran Brotherhood study,
based on much smaller numbers, an increased relative risk for ever smokers (1.8) and former smokers
(1.9) is reported, but no dose response with CPD,
categorized at 1-19,20-29, and 30 or more CPD. As a
substantial proportion, maybe 40-50% of those
smoking at study entry had quit smoking in the 1620-year period of follow-up [16] this would introduce,
as an artifact, a dose-response relation between
amount smoked and prostate cancer mortality, provided the heavy smokers at study entry are less likely
to subsequently quit than the light smokers. Such
differential quitting by exposure level is very plausible, as already noted by others [69]. All things being
equal, this might result in an underestimate of the
effect of smoking per se, as has been stressed by
Hsing et al. [48].
CONCLUSIONS
On the basis of data presently available, neither a
clinically nor a statistically sigruhcant association between smoking and prostate cancer seems likely, but
it cannot be ruled out entirely. In addition, reported
positive associations between smoking and prostate
cancer are unlikely to be causal. The positive associations reported by a limited number of cohort studies
cannot be ignored because of their study size, but
their results are hard to interpret because smoking
status was only available at study entry, and during
the follow-up period (ranging from 16 to 26 years)
dramatic changes in smoking behavior and the composition of cigarettes took place. Because of the design used in these studies, the effects of these
changes could not be evaluated appropriately. It
should be relatively easy, however, to collect additional information on lifetime smoking patterns in
several ongoing case-control and cohort studies. This
is likely to provide a more definitive answer as to
whether smoking and prostate cancer are causally related, and if so, how large the excess risk excess is
likely to be. Because smoking is not likely to be re-
lated to prostate cancer, the association between
other purported risk factors and prostate cancer is not
likely to be confounded by the incomplete measurement and control for smoking habits. Therefore, the
collection of complete smoking information is less
critical for studies of prostate cancer than in patients
with other diseases.
FUTURE NEEDS
For case-control studies, a systematic evaluation of
dose-response associations of smoking exposure and
prostate cancer in future studies is recommended.
These include, for smokers, age started smoking,
number of years smoked, CPD, and brand of cigarettes smoked, and for nonsmokers also the number
of years since quitting, if applicable. Information
should also be collected on the amount and brand of
cigarettes smoked and on the inhalation patterns in
defined time periods, to allow for an estimate of lifetime tar exposure. The lifetime (or cumulative) tar
exposure is calculated by summing over the different
brands of cigarettes smoked in defined periods the tar
content for each cigarette, the number of days the
brand was smoked, and the number of cigarettes of
each brand consumed per day [70].
For cohort studies, a standard set of outcomes for
reporting is needed. At a minimum these should include the relative risk of those smoking 1-9, 10-20,
21-30, 41 + CPD vs. never smokers, the risk of current (all CPDs aggregated) vs. never smokers, and
the risk of former vs. never smokers. In addition,
adequate information needs to be collected at study
entry and at regular follow-up intervals to allow for
an estimate of lifetime tar exposure. ORs and RRs
should be provided with point estimates and 95% CIS
accurate to the second decimal point, to allow inverse
variance weighing of the point estimates. If, in future, case-control and cohort studies also focus on
collecting adequate information on lifetime tar exposure it may be possible to obtain better risk estimates
of the association between smoking and prostate cancer incidence and mortality.
ACKNOWLEDGMENTS
Dr.A. W. Hsing kindly provided additional information on the U.S.Veterans study and brought two
of the reports on smoking and prostate cancer to my
attention. The concept of effective sample size
emerged from a fruitful discussion with Dr. E. Zang.
Figure 2 on the changing composition of cigarettes
over time was provided by Dr. D. Hoffmann. The
tables were typed by Pat Lamb. Their help is gratefully acknowledged. Supported in part by Grant CA
17613 from the National Cancer Institute.
Prostate Cancer and Smoking
NOTE ADDED IN PROOF
We identified an additional cohort study from Norway [71] which was added to the references. The
study did not show an excess risk of smoking.
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