Table 1 reproduces the results from the publication from the Hugosson et al (9) publication. The table provides a detailed description of the ‘Eighteen-year follow-up of the Göteborg Randomized Population- based Prostate Cancer Screening Trial’. A total of 19899 participants were included in this experimental study. Half of the invited participants were allocated to the screening and half to the control group. 7647 of the 9950 invited participants (77%) accepted the invitation to screening but 2303 of 9950 (23%) refused this invitation. Table 1 also shows the number of prostate cancer cases detected, the death from prostate cancer, the death from all causes, and the number of metastatic prostate cancer. Using these data, it can be demonstrated that the death from prostate cancer among patients with detected prostate cancer is twice as high in the not invited population (12.6%) as compared to the invited population (5.6%). The same ratio is found when comparing the development of metastatic disease (18.6% versus 8.3%). Both data sets are contrasting the all-cause mortality rates that are identical in the invited and not invited groups.
If those who declined screening were equivalent to people randomly assigned not be offered screening, we would expect equal detection rates in the two groups. However, the rate of detection for those offered but refused was about half as high (5.3%) in comparison to those who were not offered screening (9.6%). The detection rate among those who accepted the invitation for screening was 16.6%. The “intention to treat” method combines the those who accepted or refused an offer for screening. When considered by intention to treat, there were fewer prostate cancer deaths in the invited group in comparison to those not invited (0.8% vs 1.2). However, there were no differences in all-cause mortality (28.6% vs 28.7%).
Table 1
Basic information from the detailed report by Hugosson et al. (9).
#
|
Invitated to screening
|
Yes
|
No
|
All
|
01
|
Self-selected persons who …..
the invitation
|
Accepted
|
Declined
|
All
|
All
|
Total
|
02
|
Number of persons
|
7647
|
2303
|
9950
|
9949
|
19899
|
03
|
Prostate cancer detected
|
1272
|
124
|
1396
|
962
|
2358
|
04
|
Death from prostate cancer
|
51
|
28
|
79
|
122
|
201
|
05
|
Death from all causes
|
1763
|
1081
|
2844
|
2857
|
5701
|
06
|
Metastatic prostate cancer
|
47
|
69
|
116
|
179
|
295
|
Effects of Consent
The synopsis in Fig. 1 highlights the differences among the subgroups in this study. It shows that not all individuals who were invited to participate in a screening program took advantage of this offer. According to the study protocol the group of participants who was invited to screening was asked to provide informed consent. As the consent was obtained only after randomization it is unclear (and not described in the original publication) whether or not an consent was also requested from invited participants with negative screening results (Fig. 1 cells with blue background) and from participants invited to screening who refused the screening offer (Fig. 1 the cell with yellow background of the invited group).
Calculation of missing details
The information generated by randomization was used for calculation of the missing details in the group of participants who were not invited for screening. The invited and not invited groups were large enough to assume a fairly equal distribution of subpopulations in the two groups. Assuming that those with a good prognosis are most likely to accept a screening offer, randomization should result in equal distributions of participants with assumed good (accepting the screening offer) or poor prognosis (refusing the screening offer). Due to random allocation the numbers of refusers (assumed poor prognosis) will be identical in the group invited for screening or not invited (control group). The numbers of participants not invited to screening with assumed good prognosis can be calculated by the difference of all not invited and the not invited participants with assumed poor prognosis. These calculated data are presented in Table 2.
Table 2
Calculation of missing data. Due to the random allocation of participants of the screened (columns A, B, C) and not screened groups (column D, E, F) should be equally distributed. The distribution of participants who refused the invitation to screening with assumed poor prognosis in the invited group (column B) will be similar to the distribution participants with assumed poor prognosis in the control group (column E). The difference of the total numbers of participants in the control group (column F) and the number of the participants with poor prognosis (E) will result in the number of participants in the control group with assumed good prognosis (column D). The data in column (E) are shown in (brackets) to indicate the numbers in column (E) are similar to the numbers in column B. To avoid an overload of information lines 02–04 of Table 1 were eliminated in Table 2.
Line
|
Columns A-F
|
A
accepted/good prognosis
|
B
refused/poor prognosis
|
C
Total in-
invited groop
|
D
not invited/good prognosis
|
(E)
not invided/poor prognosis
|
F
Total in control
|
01
|
Invitation
|
Invited to screening
|
Not invited to screening
|
05
|
Number of particip.
|
7647
|
2303
|
9950
|
7646
|
(2303)
|
9949
|
06
|
Prostate ca. detected
|
1272
|
124
|
1396
|
838
|
(124)
|
962
|
07
|
Deaths from prost. ca
|
51
|
28
|
79
|
94
|
(28)
|
122
|
08
|
Deaths from all causes
|
1763
|
1081
|
2844
|
1776
|
(1081)
|
2857
|
09
|
Metatstatic prost. Ca
|
47
|
69
|
116
|
110
|
(69)
|
179
|
The completion of the missing numbers enables the calculation of five indicators for assessment of the efficacy of prostate cancer screening.
The indicators of efficacy
The five indicators of efficacy are shown in Table 3: the Incidence of diagnosed Prostate Cancer (IPC line 10), the Disease Specific Mortality (DSM line 11), the All Cause Mortality (ACM line 12), the Lethality from Prostate Cancer (LPC line 13), and the of Advanced (metastatic) Stage of Disease (ASD line 14). These data provide three types of specific information. It explains the detailed decisions and assumptions that were made by the investigator, the participants, and the attending physicians.
The investigator selected the participants from a data base and used the randomization for allocation of the participants to either the groups invited or not invited for screening. The attending physician and investigators recorded the participants’ decision to accept or to refuse the invitation and offered the screening according to the individual participant’s decision. The investigator also derived the assumed prognosis from the individual participant’s decisions: a good prognosis is assumed if the invitation was accepted but poor prognosis if it was refused.
The Informed Consent
According to the original publications (9, 10) Informed Consent (IC) was obtained only from participants who were invited to screening but not from the not invited group. The original publication does, however, not describe if all invited participants were asked to provide an IC or only those who accepted the invitation for screening or those who were offered treatment due to a positive screening result. This information is important for ethical, epidemiological, medical and economic reasons. Lacking information on the IC has to be considered for the interpretation of the results.
Table 3
The upper part of this synopsis replicates the results of Table 2. This synopsis provides three types of information. First, the descriptions of the two study groups: invited or not invited (line 1) and its four subgroups: invited participants who accepted or refused the invitation (line 2 col. A and B) and not invited participants (line 2 col D and E). The assumed prognoses and the obtained IC in these four subgroups are described in line 3 and 4. The second type of information includes the numbers in the four subgroups of participants, of detected prostate cancer, of death from prostate cancer, of death from all causes, and of metastatic prostate cancers. The third type of information describes the indicators [in brackets the lines used for calculation] that express the effects of prostate cancer screening mostly but not exclusively under experimental study conditions. These indicators are the incidence of prostate cancer (IPC line 10), the disease specific mortality (DSM line 11), the all-cause mortality (ACM line 12), the lethality from prostate cancer (line 13), and the rate of metastatic disease (RMD line 14).
Line
|
Columns A-F
|
A
|
B
|
C
|
D
|
(E)
|
F
|
01
|
Invitation
|
Invited to screening
|
Not invited to screening
|
02
|
Particip. self-selection
|
Accepted
|
Refused
|
All invited
|
No invit.
|
No invit.
|
All not invit
|
03
|
Assumed prognosis
|
Good
|
Poor
|
Mixed
|
Good
|
Poor
|
Mixed
|
04
|
Informed Consent (IC)
|
Explicitly
|
Unlikely
|
Partially
|
Implicitly f ext. screen.
|
Partially
|
05
|
Number of particip.
|
7647
|
2303
|
9950
|
7646
|
(2303)
|
9949
|
06
|
Prostate ca. detected
|
1272
|
124
|
1396
|
838
|
(124)
|
962
|
07
|
Deaths from prost. ca
|
51
|
28
|
79
|
94
|
(28)
|
122
|
08
|
Deaths from all causes
|
1763
|
1081
|
2844
|
1776
|
(1081)
|
2857
|
09
|
Metatstatic prost. Ca
|
47
|
69
|
116
|
110
|
(69)
|
179
|
10
|
IPC [line 6/5]
|
16,6%
|
5,38%
|
14,0%
|
11,0%
|
Numbers in col (E) were copied from col B due to randomization
|
9,67%
|
11
|
DSM [line 7/5]
|
0,67%
|
1,22%
|
0,79%
|
1,23%
|
1,23%
|
12
|
ACM [line 8/5]
|
23,1%
|
46,9%
|
28,6%
|
23,2%
|
28,7%
|
13
|
LPC [line 7/6]
|
4,01%
|
22,6%
|
5,66%
|
11,2%
|
13,8%
|
14
|
RMD [line 9/5]
|
0,61%
|
3,00%
|
1,17%
|
1,44%
|
1,80%
|
Assessment of the Efficacy of Prostate Cancer Screening
Line 10 in Table 4 shows the odds ratios of incidences of prostate cancer (i.e. the pathologist’s assignment of the diagnosis ‘prostate cancer’) seems to be higher in populations with assumed good prognosis than subgroups with poor prognosis. The likely reason for this difference is the population with assumed good prognosis more often accepts screening than the subgroups with assumed poor prognosis.
Table 4
Assessment of efficacy of prostate cancer screening based on the results of Hugosson et. al (9, 10). The odds ratios of the incidences of prostate cancer, the disease specific mortalities, the all- cause mortalities, the lethality from prostate cancer, and the risks of advanced stage of disease are compared in three pairs of target populations. Left column: the good prognosis subgroups with or without screening. Middle column: not invited groups with good or poor prognosis. Right column: the groups of all invited versus all not invited participants.
Effects of
Effects on
|
Screen/No screen in subgroups with assu. good progn.
|
Assumed good / poor
prognosis
|
Screening of invited /not invi-ted participants
|
Odds ratios
calculated from columns in Table 3
|
[A / D
|
[D / E]
|
[C / F]
|
Line 10: Incidence of Prostate Ca. (IPC)
Line 11: Disease spec. mortality (DSM)
|
1.5
0.5
|
2.0
1.0
|
1.5
0.6
|
Line 12: All-cause mortality (ACM)
|
1.0
|
0.5
|
1.0
|
Line 13: Lethality from Prost. Ca. (LPC)
Line 14: Risk adv stage disease (metas.)
|
0.4
0.4
|
0.5
0.5
|
0.4
0.7
|
Line 11 shows the disease specific mortality depends on screening: when screened and not screened groups are compared (left and right columns of Tab. IV) the odds of DSM is < 1 because the screened groups include participants with better prognosis than the not screened groups. This is not true for the middle column where the odds rate was 1. Neither of the two comparison groups were screened.
Line 12 of Table 4 shows that screening has no effect on the all-cause mortality when either subgroups with good prognosis who accepted frequent screening were compared with the corresponding subgroup that was not offered screening (left column) or all participants with or without an offer to be screened were compared (right column). The ACM odds ratio of 0.5 in the middle column seems to be plausible because this column compares participants with a good versus a poor prognosis. Neither of these subgroups was offered screening within the study but the subgroup with good prognosis may have asked more often for external screening than the subgroup with poor prognosis. This information was not presented in the analyzed publication.
Line 13 seems to demonstrate that the lethality from prostate cancer is always lower in screened than in not screened groups. Another explanation for these data is the difference in the prognosis, which is likely to be better in the screened than in the not screened groups. A third possible explanation is potential biases in both types of information used for the calculation of LPC. These two types of information that are sensitive to bias are the diagnosis of prostate cancer and prostate cancer as cause of death. From a scientific perspective the numbers of participants in a study and the numbers of observed deaths are numbers least likely to be affected by bias.
Line 14 shows a problem similar to lines 10 and 13. The caveat in this line is related to the diagnosis of metastases from prostate cancer. We are not sure that a PSA concentration of > 100 ng/ml is a reliable indicator for the diagnosis of advanced stage i.e. metastatic prostate cancer as some authors have suggested (9). Numbers based on the reduction of metastatic prostate cancer that are not based on the demonstration of either osteolytic or osteoplastic bone metastases in association with solid histopathologic data that confirm prostate cancer as primary tumor should be interpreted with caution.