Tag Archives: prostate cancer

To PSA or not to PSA

In light of the controversy over the Ministry of Health’s pamphlet on prostate cancer I thought I would repost a post I published in May 2012:

___________________________________________________

As a male, 40 mumble years old, do I do it?  Do I get a prostate exam and PSA test?  Do I plan to keep doing tests every few years?

PSA (prostate specific antigen) is a blood test where elevated levels may indicate the presence of prostate cancer.  A powerful group, the US Preventative Services Task Force has come out against screening with PSA giving the test its lowest (D) grade.  They conclude “that many men are harmed as a result of prostate cancer screening and few, if any, benefit.”  Strong words. TV3 (misleadingly, but that’s another story!) and other media reported on this last night. The response of the Urological Society (at least its president) is to reject the report and urges men “not to be deterred” and to “discuss the PSA blood test with their GP.

This is approximately how my conversation went a couple of years ago.

GP: We’ll do a PSA test while we are at it.

ME:  Isn’t that a waste of time? Doesn’t it have a lot of false positives?

GP: Yes, but we can monitor for changes.

Hmmm…so it is not just the value of the test, but how it changes in time that is important.  A quick check on the internet I find that this is called the PSA “velocity.”  Interestingly in the evidence provided by the US Task Force I can find no mention of PSA velocity.

In the meantime, a quick check on the Canterbury Health Labs web site (see here) tells me that the test has a reference range of 0 to 4.0 ug/L (this is a concentration in plasma).  If a test is above this range a GP is likely to want to discuss it with you and may recommend a biopsy.

This is where life gets interesting.  A couple of weeks ago I talked of “False Positives” and introduced the diagram below.  A “False Positive” for myself would have been a PSA above 4.0 ug/L which didn’t turn out to be cancer.  The main issue with PSA tests is the high number of False Positives.  The Task Force suggested that in a screening regime after 3 or 4 tests (over several years) 12 to 13% of participants have a positive test.  Most, though, are False Positives.  Approximately 80% of Positive tests are False Positives!  Consider this – if screening happened in NZ and 500,000 men had a test every 5 years then after 15 to 20 years 500,000 * 0.12 *0.8 = 4800 men will have had a False Positive test.  Another 1200 a True Positive test.

Ideally every test result will lie in the dark blue (true negative) or dark red (true positive). In reality, there is always a few false positives and false negatives [A good test would have few (the narrow ellipse), a poor test would have many (broader ellipse)].

Importantly, the Urological Society put it this way “The PSA blood test does not diagnose prostate cancer. But it raises a red flag and identifies those men who need to have prostate cancer excluded through further investigation via a prostate biopsy.”

PSA does not diagnose – this is a very important point that a GP must communicate BEFORE a test is done.  I would be surprised if even 10% of men realize that PSA does not a diagnose.  So what happens to all the False Positives and True Positives?  This is what the Task Force focused on.

First they asked “Does PSA-Based Screening Decrease Prostate Cancer–Specific or All-Cause Mortality? Does PSA-Based Screening Decrease Prostate Cancer–Specific or All-Cause Mortality?

There was no clear evidence it does (contradictory studies).  In their useful “stats at a glance” publication they state “1 man in 1,000 – at most – avoids death from prostate cancer because of screening.”

If this is so, then it could be worth it (by the way – at a cost of $11.92 + GST + cost of GP visit – say $60 (low), then I estimate screening of 100,000 men a year would cost a minimum of $7.2M annually in NZ).

It is the next questions of the Task Force that are revealing.  The looked at the harms of screening.  The harms of those with Positive test (True or False) and then the harm to those finally diagnosed with prostate cancer.  Again the summary is revealing:

Most prostate cancers found by PSA screening are slow growing, not life threatening, and will not cause a man any harm during his lifetime. However, there is currently no way to determine which cancers are likely to threaten a man’s health and which will not. As a result, almost all men with PSA-detected prostate cancer opt to receive treatment. In addition to the frequent complications of biopsy that lead to a cancer diagnosis, there can be serious harms from treatment of screen-detected prostate cancer.

For every 1,000 men who are screened with the PSA test:

  • 30 to 40 men will develop erectile dysfunction or urinary incontinence due to treatment
  • 2 men will experience a serious cardiovascular event, such as a heart attack, due to treatment
  • 1 man will develop a serious blood clot in his leg or lungs due to treatment 


For every 3,000 men who are screened with the PSA test:

  • 1 man will die due to complications from surgical treatment

And they did not attempt to assess social or psychological harm!  Imagine the conversation at home:

Man: Hi honey, I’m home.  I got a positive PSA test today.

Woman:  That’s nice dear.  Did you get an appointment for a biopsy.

Man:  Yes, in 3 months time.

Woman: Great.  Shall we go out for dinner?

Somehow, I don’t think it would be like that, except perhaps the waiting time for a next appointment.

So where does this leave us.  My opinion, for what it is worth, is that:

  1. A PSA screening program should not take place in New Zealand.
  2. GPs should use PSA tests only where there are other risk factors
  3. Prior to any other procedure, repeat tests of positives should be done under strict conditions. Particularly the diet of the person involved should be changed to minimize the risk of false positives (there is still debate about the role of diet in false positives – so some research should be done at the same time: “Does changing diet change PSA levels in the short term?”).  Men – you can ask for this!
  4. GPs should explain that:
  •            a positive test does not mean cancer (most probably already do explain this, but it worth emphasizing),
  •            there are risks with biopsies, and
  •            there are great risks with treatment (prostectomy or radiation normally).

I qualify this with what appears to me to be a lack of assessment of the benefit of “changes in PSA” levels.  The sort of question which comes to mind is “How accurate is the diagnosis of a 2 ug/L or 100% increase (say) in PSA over 5 years?”

I wonder, would you have a PSA test?

Advertisements

Prostate cancer and omega 3

The media is in a feeding frenzy with reports of a link between Omega 3 and Prostate Cancer.  Here’s a sample:

Link Between Omega-3 Fatty Acids and Increased Prostate Cancer Risk Confirmed (Science Daily)
Omega-3 supplements ‘could raise prostate cancer risk’ (Telegraph)
Omega-3 supplements linked to prostate cancer (Fox)
Omega 3 could increase cancer risk (TV3)

So, what’s the fuss?  The fuss is about a study published online yesterday in the Journal of the National Cancer Institute:

Brasky, T. M., Darke, A. K., Song, X., Tangen, C. M., Goodman, P. J., Thompson, I. M., et al. (2013). Plasma Phospholipid Fatty Acids and Prostate cancer Risk in the SELECT trial. Journal Of The National Cancer Institute, 1–10. doi:10.1093/jnci/djt174/-/DC1

The article is behind a paywall, so I’m not sure how many of the journalists have bothered to read it instead of relying on press releases.  I’ve access to the paper through my university, so here is a synopsis for the lay reader (bearing in mind I am not an expert in either omega 3 or cancer).

The thinking in the general public: Prostate cancer bad, Omega 3 good, therefore Omega 3 may prevent/delay prostate cancer

The thinking of the scientists: Is there a link between phospholipids (including omega 3) and prostate cancer?

The subjects studied:  Participants were enrolled in a trial of Vitamin E supplementation verse Placebo.  They were all male, from the US, Canada or Peurto Rico, aged 50+ if black (the medical literature uses this description), or 55+ if not, had no history of prostate cancer and with a PSA (prostate-specific antigen) test of <4ng/ml at the start of the study.  They were enrolled between July 2001 and May 2004.  While 35,533 men were enrolled in the trial, in this study only 2273 were studied.  These consisted of 834 patients who had prostate cancer diagnosed prior to 1 January 2008 and 1364 “matched” subjects who had no prostate cancer diagnosed in that time.  This is called a case-controlled study.  The “matching” is a statistical process whereby they make sure the two groups being compared (those with and without cancer) have certain demographic features in common on average.  In this case the groups had similar age ranges and similar ethnicities.  The cancer group was further divided into those with low and those with high grade cancers.

The methods:  Blood samples taken when patients were recruited and the total fatty acid content along with 4 types of Omega-3 fatty acids, 2 types of Omega-6 fatty acids, and 3 types of Trans-fatty acids were measured. The mean (average) proportions of each of the types of fatty acids (compared with total fatty acid) were compared between the No cancer and the Prostate Cancer groups.

The results:  Those with cancer had on average a greater proportion of each of  three of the kinds of Omega-3 fatty acids than those without cancer.  The p values were 0.03, <0.001, 0.006 (see here for an explanation of p values).  The p values for the two Omega-6 were higher (therefore more likely to be arrived at by chance) at 0.17 each.  The Trans-Fatt p values were 0.048, 0.08, 0.002. At this point it is very important to remember that not all those with cancer had high proportions of Omega-3 – it was the average that was higher.  An analysis comparing the 25% of subjects with the lowest Omega-3 (combination of the three Omega-3s) values with those with the highest 25% showed that the risk of prostate cancer was between 9 and 88% greater (with 95% confidence that this was not just by chance), ie a Hazard Ratio of 1.43 (95%CI 1.01 to 1.88).  Considering only those with the highest grade of cancer the Hazard Ratio was 1.71 (95%CI 1.0 to 2.94).

The authors performed a multivariable analysis.  That is when they check to see if other factors may be influencing the results.  They say that for Omega-3:

The continuous multi-variable-adjusted hazard ratios predicting total, …prostate cancer risk, [was] 1.16 (95% CI = 0.98 to 1.36),

This means that Omega-3 proportions changed the risk of getting prostate cancer by between a 2% decrease (100*(1-0.98)) and 36% increase (100*(1.346-1)) when other factors (not stated what) are accounted for.  This is what the 95% CI (Confidence interval) suggests.  The 1.16 is merely somewhere near the middle of the change in risk (16% higher).  It is the confidence interval that matters.  When it crosses 1, as it does here, it is not normally considered very important (ie not “statistically significant” as is often said).

The authors then conducted a meta-analysis for the Relative Risk of getting prostate cancer for two types of Omega-3 (DHA and EPA) and Omega-3 total fatty acid.  A meta-analysis is where they gather up all the studies and combine the results together.  In this case there were 7 studies (including the present one) which reported DHA and EPA and 4 which reported totals.  The results were

EPA:  RR = 1.07 (95%CI 0.95 to 1.21)
DHA: RR=1.16 (95%CI 1.03 to 1.31)
Total: RR=1.14 (95% CI 0.99 to 1.32)

Remember it is the 95% CI that is most important.  In this case only DHA creeps above 1 for the 95% CI.  Remember also that RR (Relative Risk) is a comparison of the rates of cancer between those with the level of Omega-3 among the lowest 20% and among the highest 20%.

The Conclusions:  The authors conclude

…these findings contradict the expectation that high consumption of long-chain ω-3 fatty acids and low consumption of ω-6 fatty acids would reduce the risk of prostate cancer.

This sounds reasonable under the assumption that consuming omega-3 (eg in supplements) actually increases the proportion of omega-3 in the blood.  They also state

It is unclear why high levels of long-chain ω-3 PUFA would increase prostate cancer risk,

What the media said:  TV3 borrowing from Sky, had a graphic with the word “Supplements” prominent and they talked of a 71% increased risk of high grade prostate cancer and 43% increased risk overall.  As we’ve seen these numbers are not what is relevant, the confidence intervals are – this adds a lot more uncertainty to the results (but not such good TV).  Also, they ignored the meta-analysis entirely (numbers not so big or interesting). They said nothing about the age range etc.  Finally, and most importantly, the study was not a study of supplements!  We have no idea why some participants had higher Omega-3 than others.  Some may have been because of supplements, some because of fish eating, some simply because of their own body composition and own metabolism.

My conclusion:  The study did not show that supplementation of Omega-3 is risky.  Nor did it show that supplementation is beneficial. It simply was not a study of supplementation. It did show that elevated proportions of Omega-3 fatty acids are possibly associated with increased risk of prostate cancer in men 50+ (black) and 55+ (non-black). Remember, too, that this is talking about relative risk.  The overall prostate cancer risk during the study period was just 2.35%.  If I’ve done my math right, then those in the top 25% of Omega-3 have an absolute risk of 2.77% (95%CI 2.12% to 3.65%).

 

To PSA or not to PSA

As a male, 40 mumble years old, do I do it?  Do I get a prostate exam and PSA test?  Do I plan to keep doing tests every few years?

PSA (prostate specific antigen) is a blood test where elevated levels may indicate the presence of prostate cancer.  A powerful group, the US Preventative Services Task Force has come out against screening with PSA giving the test its lowest (D) grade.  They conclude “that many men are harmed as a result of prostate cancer screening and few, if any, benefit.”  Strong words. TV3 (misleadingly, but that’s another story!) and other media reported on this last night. The response of the Urological Society (at least its president) is to reject the report and urges men “not to be deterred” and to “discuss the PSA blood test with their GP.

This is approximately how my conversation went a couple of years ago.

GP: We’ll do a PSA test while we are at it.

ME:  Isn’t that a waste of time? Doesn’t it have a lot of false positives?

GP: Yes, but we can monitor for changes.

Hmmm…so it is not just the value of the test, but how it changes in time that is important.  A quick check on the internet I find that this is called the PSA “velocity.”  Interestingly in the evidence provided by the US Task Force I can find no mention of PSA velocity.

In the meantime, a quick check on the Canterbury Health Labs web site (see here) tells me that the test has a reference range of 0 to 4.0 ug/L (this is a concentration in plasma).  If a test is above this range a GP is likely to want to discuss it with you and may recommend a biopsy.

This is where life gets interesting.  A couple of weeks ago I talked of “False Positives” and introduced the diagram below.  A “False Positive” for myself would have been a PSA above 4.0 ug/L which didn’t turn out to be cancer.  The main issue with PSA tests is the high number of False Positives.  The Task Force suggested that in a screening regime after 3 or 4 tests (over several years) 12 to 13% of participants have a positive test.  Most, though, are False Positives.  Approximately 80% of Positive tests are False Positives!  Consider this – if screening happened in NZ and 500,000 men had a test every 5 years then after 15 to 20 years 500,000 * 0.12 *0.8 = 4800 men will have had a False Positive test.  Another 1200 a True Positive test.

Ideally every test result will lie in the dark blue (true negative) or dark red (true positive). In reality, there is always a few false positives and false negatives [A good test would have few (the narrow ellipse), a poor test would have many (broader ellipse)].

Importantly, the Urological Society put it this way “The PSA blood test does not diagnose prostate cancer. But it raises a red flag and identifies those men who need to have prostate cancer excluded through further investigation via a prostate biopsy.”

PSA does not diagnose – this is a very important point that a GP must communicate BEFORE a test is done.  I would be surprised if even 10% of men realize that PSA does not a diagnose.  So what happens to all the False Positives and True Positives?  This is what the Task Force focused on.

First they asked “Does PSA-Based Screening Decrease Prostate Cancer–Specific or All-Cause Mortality? Does PSA-Based Screening Decrease Prostate Cancer–Specific or All-Cause Mortality?

There was no clear evidence it does (contradictory studies).  In their useful “stats at a glance” publication they state “1 man in 1,000 – at most – avoids death from prostate cancer because of screening.”

If this is so, then it could be worth it (by the way – at a cost of $11.92 + GST + cost of GP visit – say $60 (low), then I estimate screening of 100,000 men a year would cost a minimum of $7.2M annually in NZ).

It is the next questions of the Task Force that are revealing.  The looked at the harms of screening.  The harms of those with Positive test (True or False) and then the harm to those finally diagnosed with prostate cancer.  Again the summary is revealing:

Most prostate cancers found by PSA screening are slow growing, not life threatening, and will not cause a man any harm during his lifetime. However, there is currently no way to determine which cancers are likely to threaten a man’s health and which will not. As a result, almost all men with PSA-detected prostate cancer opt to receive treatment. In addition to the frequent complications of biopsy that lead to a cancer diagnosis, there can be serious harms from treatment of screen-detected prostate cancer.

For every 1,000 men who are screened with the PSA test:

  • 30 to 40 men will develop erectile dysfunction or urinary incontinence due to treatment
  • 2 men will experience a serious cardiovascular event, such as a heart attack, due to treatment
  • 1 man will develop a serious blood clot in his leg or lungs due to treatment 


For every 3,000 men who are screened with the PSA test:

  • 1 man will die due to complications from surgical treatment

And they did not attempt to assess social or psychological harm!  Imagine the conversation at home:

Man: Hi honey, I’m home.  I got a positive PSA test today.

Woman:  That’s nice dear.  Did you get an appointment for a biopsy.

Man:  Yes, in 3 months time.

Woman: Great.  Shall we go out for dinner?

Somehow, I don’t think it would be like that, except perhaps the waiting time for a next appointment.

So where does this leave us.  My opinion, for what it is worth, is that:

  1. A PSA screening program should not take place in New Zealand.
  2. GPs should use PSA tests only where there are other risk factors
  3. Prior to any other procedure, repeat tests of positives should be done under strict conditions. Particularly the diet of the person involved should be changed to minimize the risk of false positives (there is still debate about the role of diet in false positives – so some research should be done at the same time: “Does changing diet change PSA levels in the short term?”).  Men – you can ask for this!
  4. GPs should explain that:
  •            a positive test does not mean cancer (most probably already do explain this, but it worth emphasizing),
  •            there are risks with biopsies, and
  •            there are great risks with treatment (prostectomy or radiation normally).

I qualify this with what appears to me to be a lack of assessment of the benefit of “changes in PSA” levels.  The sort of question which comes to mind is “How accurate is the diagnosis of a 2 ug/L or 100% increase (say) in PSA over 5 years?”

I wonder, would you have a PSA test?