EURURO Vol. 72 No. 6

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event of interest is treated as a competing event. Thus, the
crude probability of CVD will be decreased by a high
number of competing events (eg, death from prostate
cancer). At 10-yr follow-up, men on GnRH agonists in our
study had a higher probability of CVD and a lower
probability of prostate cancer death in comparison to
men who underwent orchiectomy.
Net probability refers to the hypothetical situation in
which only the event of interest can occur. All other events
are censored and there is no influence from competing
events on risk; this is the preferred study design for
investigating causality . We found that the net
probability of both CVD and prostate cancer death were
higher for men who underwent orchiectomy than for men
on GnRH agonists. The results from these head-to-head
comparisons are in accordance with a Chinese study of
297 men on GnRH agonists and 387 men who underwent
orchiectomy Furthermore, previous studies using
PCBaSe that included 5000 men who underwent orchiecto-
my and 20 000 men on GnRH agonists showed that these
two ADT modalities were associated with a similar increase
in CVD risk and fracture risk in comparison to the
background male population
By contrast, our results differ from those of three other
large observational studies . Two of the studies, a
Surveillance, Epidemiology and End Results (SEER)–Medi-
care database study including 73 196men with locoregional
prostate cancer and a Danish nationwide, population-
based study including more than 30 000 prostate cancer
cases , investigated the risk of CVD for men managed
with orchiectomy or medical ADT (in the Danish study both
GnRH agonists and antiandrogens) to that for men with
prostate cancer not on ADT. Both studies found a higher risk
of CVD for men on GnRH agonists compared to men not on
ADT, whereas the risk of CVD was similar for men who had
undergone orchiectomy and men not on ADT.
The third study, also a SEER study, included men with
metastatic prostate cancer primarily managed with ADT
during a 15-yr period, of whom 2866 men received GnRH
agonists and 429 men underwent orchiectomy. In a direct
comparison between the two ADT modalities, the crude
probability of CVD and of fractures and diabetes was lower
after orchiectomy in comparison to GnRH agonists . It is
difficult to conceive a biologicalmechanismfor the lower risk
of fractures after orchiectomy compared to GnRH agonists.
The risk of fractures increases with lower levels of androgens
and, on average, androgen levels are slightly higher in
men on GnRH agonists than in men who have undergone
orchiectomy Thus, confounding is a likely explanation
for the unexpected results for fractures and could also have
contributed to the associationwith CVD. Furthermore, in this
SEER study, there was no statistically significant difference in
net probability, the preferred method for investigation of
causality, between GnRH agonists and orchiectomy for any
outcome, in accordance with our results.
Taken together, the results from our study and all the
cited studies do not provide evidence that warrants a
change in the recommendations for use of ADT for advanced
prostate cancer from GnRH agonists to orchiectomy.
5. Conclusions
In this nationwide, population-based observational study
there was no increase in the risk of CVD among men on
GnRH agonists compared to men who had undergone
orchiectomy in three separate analytical approaches. Our
study provides no evidence in favour of changing the
current standard ADT for prostate cancer.
Author contributions: [21_TD$DIFF]Fredrik [22_TD$DIFF]Sandin had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Stattin, Thomsen, Garmo, Sandin.
Acquisition of data: Stattin, Robinson,[6_TD$DIFF] Lissbrant, Ahlgren.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: Thomsen, Stattin.
Critical revision of the manuscript for important intellectual content: All
authors.
Statistical analysis: Sandin, [23_TD$DIFF]Garmo, Stattin, Thomsen.
Obtaining funding: Stattin.
Administrative, technical, or material support: None.
Supervision: None.
Other: None.
Financial disclosures: Frederik Birkebæk Thomsen certifies that all
conflicts of interest, including specific financial interests and relationships
and affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultancies,
honoraria, stock ownership or options, expert testimony, royalties, or
patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: This work was supported by
The Swedish Research Council (825-2012-5047) and The Swedish Cancer
Foundation (16 0700). Frederik Birkebæk Thomsen is supported by a
research grant from IMK Almene Fond. The sponsors had no involvement
with the planning, execution, or completion of the study.
Acknowledgments: This project was made possible by the continuous
work of the National Prostate Cancer Register of Sweden steering group:
Pa¨r Stattin (chairman), Anders Widmark, Camilla Thellenberg Karlsson,
Ove Andre´n, Ann-Sofi Fransson, Magnus To¨rnblom, Stefan Carlsson,
Marie Hja¨lm-Eriksson, David Robinson, Mats Ande´n, Jonas Hugosson,
Ingela Franck Lissbrant, Maria Nyberg, Ola Bratt, Rene´ Blom, Lars Egevad,
Calle Waller, Olof Akre, Per Fransson, Eva Johansson, Fredrik Sandin, and
Karin Hellstro¨m.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
.
References
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