Presentation and critique of July 2014 paper on whether there is a link between vasectomy and prostate cancer. Presented to urology departmental meeting in London teaching hospital

1. Dr Luke Kane
2nd October 2014

2. Intro: Vasectomy & Prostate Ca
Risk
Vasectomy and Risk of Aggressive Prostate Cancer:
A 24-Year Follow-Up Study
Original report in Journal of Clinical Oncology
July 2014
US-based prospective cohort study looking at association
of vasectomy and risk of prostate cancer
Emphasis on advanced and lethal disease
Largest cohort study to date
>6000 prostate Ca cases
Nearly 50,000 participants
Longest follow up to date
24 years

3. Context: Vasectomy & Prostate Ca
Risk
Conflicting evidence between vasectomy and prostate
Ca risk
2002: Meta-analysis of 22 studies estimated a RR for
total prostate Ca of 1.37 (95% CI 1.15-1.62) for men with
and without vasectomy 1
Significant heterogeneity between studies
Numerous case control and cohort studies show no
link
1. Dennis et al. (2002)

4. Context: Health Professionals
Follow-Up Study (HPFS)
Two large cohort studies in 1993 – one retrospective
and one prospective – found a strong association
between vasectomy and prostate Ca risk2, 3
RR = 2.03 after 30y
Both based on data from HPFS 4
Prospective cohort study of >50,000 American health
professionals
The 2014 study uses the same cohort
2. Giovannucci et al. (1993)
3. Giovannucci et al. (1993)
4. http://www.hsph.harvard.edu/hpfs/index.html

5. Patients & Methods
First HPFS questionnaire in 1986; end of follow up 2010
Every two years
Those with active cancer excluded
49,405 men
Identifies those with a past vasectomy
Ascertainment of prostate cancer cases
Self reporting with confirmation by review of medical records
and pathology reports
Deaths ascertained through family reporting and searches of
National Death Index
Committee assigned cause of death with “all available data”
Excluded Localised Advanced Lethal
T1a T1, T2, N0, M0 T3b, T4, N1, M1, death Mets or death

6. Statistical Analysis
Cox proportional hazards regression to calculate
age-adjusted and multivariable-adjusted hazard
ratios and 95% CIs of:
Covariates
Race
Height
BMI
smoking
Exercise
Diabetes
FHx prostate
Ca
PSA testing
Multi-vitamins
Vit E sup.
Alcohol use
– total prostate cancer
– lethal
– advanced
– localised
– high grade
– Gleason 7
– low grade prostate
cancers
• As PSA testing is such a strong predictor of prostate Ca
diagnosis, potential for confounding effect is great
• To investigate effects of PSA testing on results they
examined a highly screened sub-cohort
• Highly screened means that from 1994-2008 they had
had a PSA test on >50% of the past questionnaires

7. Results
22% had a vasectomy at start of survey in 1986
25% by 2000
More PSA testing in those with vasectomy
In those with prostate Ca, those with vasectomy had
lower PSA levels at diagnosis
6023 cases of prostate cancer diagnosed – 12.2%
incidence
732 high grade; 811 lethal cases

8. Results: All Men
Multivariable-adjusted RR of cancer in men who had a
vasectomy compared to those without:
Not significantly associated with low-grade cancer
Total prostate cancer 1.10 (95% CI 1.04-1.17; p-value 0.001)
Lethal prostate cancer 1.19 (95% CI 1.00-1.43; p-value 0.05)
Advanced prostate cancer 1.20 (95% CI 1.03-1.40; p-value 0.02)
High grade prostate cancer 1.22 (95% CI 1.03-1.45;p-value 0.02)

9. Results: Highly Screened Sub-cohort
No association with low grade, localised or total
prostate cancer
Lethal prostate cancer 1.56 (95% CI 1.03-2.36; p-value 0.04)
High grade prostate cancer 1.28 (95% CI 0.91-1.81;p-value 0.15)

10. Discussion
Results support a positive association between
vasectomy and risk of advanced or lethal prostate
cancer
After accounting for PSA screening, vasectomy not
associated with risk of low grade or local disease
Previous cohort studies looking at link between
vasectomy and advanced disease showed increased
RR but all statistically not significant5,6,7
Previous case control studies found no significant
associations 8, 9
5. Giovanucci et al. (1993)
6. Giovanucci et al. (1993)
7. Rohrmann et al. (2005)
8. Cox et al. (2002)
9. Lesko et al. (1999 )

11. Potential for Bias & Confounding
Uses same cohort that previous studies have found link
Detection bias
Men opting for vasectomy likely to choose more medical care
than others?
More likely to see urologists at early age?
Leads to increased screening and diagnosis?
One study found that 27% of urologists report screening men
with vasectomies earlier for prostate cancer than those
without 10
You would expect detection bias to explain an increased
risk of screen-detected localised Ca in men with vasectomy
It does not explain why this study finds a higher risk of lethal
and advanced disease
10. Schwingl & Guess (2002)

12. Potential Mechanisms
Very unclear
Immunologic effects 11
Cellular proliferative changes 12
Hormonal imbalances 13
Semen protein changes 14
Infertile men have been reported to have a 2.6 fold
higher risk of high grade prostate Ca 15
?overlapping mechanism
11. Flickinger et al. (1999)
12. Pereira et al. (2006)
13. Mo et al. (1995)
14. Batruch et al. (2011)
15. Walker et al. (2010)

13. Summary
Largest and longest cohort study
In men with a history of vasectomy:
10% increased risk of prostate cancer
19% increased risk of lethal disease
In men with a vasectomy undergoing frequent PSA
screening:
56% increased risk of lethal disease
Small increase in absolute risk

14. References
Batruch et al. Proteomic analysis of seminal plasma from normal volunteers and post-vasectomy
patients identifies over 2000 proteins and candidate biomarkers of the urogenital
system. Journal of Proteome Research 10:941-953, 2011
Cox et al. Vasectomy and risk of prostate cancer. JAMA 287:3110-3115, 2002
Dennis et al. Vasectomy and the risk of prostate cancer: A meta-analysis examining vasectomy
status, age at vasectomy, and time since vasectomy. Prostate Cancer and Prostatic Diseases
5: 193-203, 2002
Flickinger et al. Post-obstruction rat sperm autoantigens identified by two-dimensional gel
electrophoresis and western blotting. Journal of Reproductve Immunology 43: 35-53, 1999
Giovanucci et al. (1993) A prospective cohort study of vasectomy and prostate cancer in US
men. JAMA 269: 873-877, 1993
Giovanucci et al. A retrospective cohort study of vasectomy and prostate cancer in US men.
JAMA 269: 878-882, 1993
Lesko et al. Vasectomy and prostate cancer. Journal of Urology 161:1848-1852 1999
Mo et al. Early and late long term effects of vasectomy on serum testosterone,
dihydrotestosterone, LH and FSH levels. Journal of Urology 154: 2065-2069, 1995
Pereira et al. Repercussions of castration and vasectomy on the ductal system of the rat ventral
prostate. Cellular Biology International 30: 169-174, 2006
Rohrmann et al. Association of vasectomy and prostate cancer among men in a Maryland
cohort. Cancer Causes & Control 16: 1189-1194, 2005
Schwingl & Guess. Safety and effectiveness of vasectomy. Fertility and Sterilisation 2000: 73
163-172
Walker et al. Increased risk of high-grade prostate cancer among infertile men. Cancer 116:
2140-2147, 2010