Sugary Drinks as the Culprit in Childhood Obesity? a RCT among Primary School Children

24 09 2012

ResearchBlogging.org Childhood obesity is a growing health problem. Since 1980, the proportion of overweighted children has almost tripled in the USA:  nowadays approximately 17% of children and adolescents are obese.  (Source: cdc.gov [6])

Common sense tells me that obesity is the result of too high calory intake without sufficient physical activity.” - which is just what the CDC states. I’m not surprised that the CDC also mentions the greater availability of high-energy-dense foods and sugary drinks at home and at school as main reasons for the increased intake of calories among children.

In my teens I already realized that sugar in sodas were just “empty calories” and I replaced tonic and cola by low calory  Rivella (and omitted sugar from tea). When my children were young I urged the day care to restrain from routinely giving lemonade (often in vain).

I was therefore a bit surprised to notice all the fuss in the Dutch newspapers [NRC] [7] about a new Dutch study [1] showing that sugary drinks contributed to obesity. My first reaction was “Duhhh?!…. so what?”.

Also, it bothered me that the researchers had performed a RCT (randomized controlled trial) in kids giving one half of them sugar-sweetened drinks and the other half sugar-free drinks. “Is it ethical to perform such a scientific “experiment” in healthy kids?”, I wondered, “giving more than 300 kids 14 kilo sugar over 18 months, without them knowing it?”

But reading the newspaper and the actual paper[1], I found that the study was very well thought out. Also ethically.

It is true that the association between sodas and weight gain has been shown before. But these studies were either observational studies, where one cannot look at the effect of sodas in isolation (kids who drink a lot of sodas often eat more junk food and watch more television: so these other life style aspects may be the real culprit) or inconclusive RCT’s (i.e. because of low sample size). Weak studies and inconclusive evidence will not convince policy makers, organizations and beverage companies (nor schools) to take action.

As explained previously in The Best Study Design… For Dummies [8] the best way to test whether an intervention has a health effect is to do a  double blind RCT, where the intervention (in this case: sugary drinks) is compared to a control (drinks with artificial sweetener instead of sugar) and where the study participants, and direct researchers do not now who receives the  actual intervention and who the phony one.

The study of Katan and his group[1] was a large, double blinded RCT with a long follow-up (18 months). The researchers recruited 641 normal-weight schoolchildren from 8 primary schools.

Importantly, only children were included in the study that normally drank sugared drinks at school (see announcement in Dutch). Thus participation in the trial only meant that half of the children received less sugar during the study-period. The researchers would have preferred drinking water as a control, but to ensure that the sugar-free and sugar-containing drinks tasted and looked essentially the same they used an artificial sweetener as a control.

The children drank 8 ounces (250 ml) of a 104-calorie sugar-sweetened or no-calorie sugar-free fruit-flavoured drink every day during 18 months.  Compliance was good as children who drank the artificially sweetened beverages had the expected level of urinary sucralose (sweetener).

At the end of the study the kids in the sugar-free group gained a kilo less weight than their peers. They also had a significant lower BMI-increase and gained less body fat.

Thus, according to Katan in the Dutch newspaper NRC[7], “it is time to get rid of the beverage vending machines”. (see NRC [6]).

But does this research really support that conclusion and does it, as some headlines state [9]: “powerfully strengthen the case against soda and other sugary drinks as culprits in the obesity epidemic?”

Rereading the paper I wondered as to the reasons why this study was performed.

If the trial was meant to find out whether putting children on artificially sweetened beverages (instead of sugary drinks) would lead to less fat gain, then why didn’t the researchers do an  intention to treat (ITT) analysis? In an ITT analysis trial participants are compared–in terms of their final results–within the groups to which they were initially randomized. This permits the pragmatic evaluation of the benefit of a treatment policy.
Suppose there were more dropouts in the intervention group, that might indicate that people had a reason not to adhere to the treatment. Indeed there were many dropouts overall: 26% of the children had stopped consuming the drinks, 29% from the sugar-free group, and 22% from the sugar group.
Interestingly, the majority of the children who stopped drinking the cans because they no longer liked the drink (68/94 versus 45/70 dropouts in the sugar-free versus the sugar group).
Ànd children who correctly assumed that the sweetened drinks were “artificially sweetened” was 21% higher than expected by chance (correct identification was 3% lower in the sugar group).
Did some children stop using the non-sugary drinks because they found the taste less nice than usual or artificial? Perhaps.

This  might indicate that replacing sugar-drinks by artificially sweetened drinks might not be as effective in “practice”.

Indeed most of the effect on the main outcome, the differences in BMI-Z score (the number of standard deviations by which a child differs from the mean in the Netherland for his or her age or sex) was “strongest” after 6 months and faded after 12 months.

Mind you, the researchers did neatly correct for the missing data by multiple imputation. As long as the children participated in the study, their changes in body weight and fat paralleled those of children who finished the study. However, the positive effect of the earlier use of non-sugary drinks faded in children who went back to drinking sugary drinks. This is not unexpected, but it underlines the point I raised above: the effect may be less drastic in the “real world”.

Another (smaller) RCT, published in the same issue of the NEJM [2](editorial in[4]), aimed to test the effect of an intervention to cut the intake of sugary drinks in obese adolescents. The intervention (home deliveries of bottled water and diet drinks for one year) led to a significant reduction in mean BMI (body mass index), but not in percentage body fat, especially in Hispanic adolescents. However at one year follow up (thus one year after the intervention had stopped) the differences between the groups evaporated again.

But perhaps the trial was “just” meant as a biological-fysiological experiment, as Hans van Maanen suggested in his critical response in de Volkskrant[10].

Indeed, the data actually show that sugar in drinks can lead to a greater increase in obesity-related parameters (and vice versa). [avoiding the endless fructose-glucose debate [11].

In the media, Katan stresses the mechanistic aspects too. He claims that children who drank the sweetened drinks, didn’t compensate for the lower intake of sugars by eating more. In the NY-times he is cited as follows[12]: “When you change the intake of liquid calories, you don’t get the effect that you get when you skip breakfast and then compensate with a larger lunch…”

This seems a logic explanation, but I can’t find any substatation in the article.

Still “food intake of the children at lunch time, shortly after the morning break when the children have consumed the study drinks”, was a secondary outcome in the original protocol!! (see the nice comparison of the two most disparate descriptions of the trial design at clinicaltrials.gov [5], partly shown in the figure below).

“Energy intake during lunchtime” was later replaced by a “sensory evaluation” (with questions like: “How satiated do you feel?”). The results, however were not reported in their current paper. That is also true for a questionnaire about dental health.

Looking at the two protocol versions I saw other striking differences. At 2009_05_28, the primary outcomes of the study are the children’s body weight (BMI z-score),waist circumference (replaced by waist to height), skin folds and bioelectrical impedance.
The latter three become secondary outcomes in the final draft. Why?

Click to enlarge (source Clinicaltrials.gov [5])

It is funny that although the main outcome is the BMI z score, the authors mainly discuss the effects on body weight and body fat in the media (but perhaps this is better understood by the audience).

Furthermore, the effect on weight is less then expected: 1 kilo instead of 2,3 kilo. And only a part is accounted for by loss in body fat: -0,55 kilo fat as measured by electrical impedance and -0,35 kilo as measured by changes in skinfold thickness. The standard deviations are enormous.

Look for instance at the primary end point (BMI z score) at 0 and 18 months in both groups. The change in this period is what counts. The difference in change between both groups from baseline is -0,13, with a P value of 0.001.

(data are based on the full cohort, with imputed data, taken from Table 2)

Sugar-free group : 0.06±1.00  [0 Mo]  –> 0.08±0.99 [18 Mo] : change = 0.02±0.41  

Sugar-group: 0.01±1.04  [0 Mo]  –> 0.15±1.06 [18 Mo] : change = 0.15±0.42 

Difference in change from baseline: −0.13 (−0.21 to −0.05) P = 0.001

Looking at these data I’m impressed by the standard deviations (replaced by standard errors in the somewhat nicer looking fig 3). What does a value of 0.01 ±1.04 represent? There is a looooot of variation (even though BMI z is corrected for age and sex). Although no statistical differences were found for baseline values between the groups the “eyeball test” tells me the sugar- group has a slight “advantage”. They seem to start with slightly lower baseline values (overall, except for body weight).

Anyway, the changes are significant….. But significance isn’t identical to relevant.

At a second look the data look less impressive than the media reports.

Another important point, raised by van Maanen[10], is that the children’s weight increases more in this study than in the normal Dutch population. 6-7 kilo instead of 3 kilo.

In conclusion, the study by the group of Katan et al is a large, unique, randomized trial, that looked at the effects of replacement of sugar by artificial sweeteners in drinks consumed by healthy school children. An effect was noticed on several “obesity-related parameters”, but the effects were not large and possibly don’t last after discontinuation of the trial.

It is important that a single factor, the sugar component in beverages is tested in isolation. This shows that sugar itself “does matter”. However, the trial does not show that sugary drinks are the main obesity  factor in childhood (as suggested in some media reports).

It is clear that the investigators feel very engaged, they really want to tackle the childhood obesity problem. But they should separate the scientific findings from common sense.

The cans fabricated for this trial were registered under the trade name Blikkie (Dutch for “Little Can”). This was to make sure that the drinks would never be sold by smart business guys using the slogan: “cans which have scientifically been proven to help to keep your child lean and healthy”.[NRC]

Still soft drink stakeholders may well argue that low calory drinks are just fine and that curbing sodas is not the magic bullet.

But it is a good start, I think.

Photo credits Cola & Obesity:  Melliegrunt Flikr [CC]

  1. de Ruyter JC, Olthof MR, Seidell JC, & Katan MB (2012). A Trial of Sugar-free or Sugar-Sweetened Beverages and Body Weight in Children. The New England journal of medicine PMID: 22998340
  2. Ebbeling CB, Feldman HA, Chomitz VR, Antonelli TA, Gortmaker SL, Osganian SK, & Ludwig DS (2012). A Randomized Trial of Sugar-Sweetened Beverages and Adolescent Body Weight. The New England journal of medicine PMID: 22998339
  3. Qi Q, Chu AY, Kang JH, Jensen MK, Curhan GC, Pasquale LR, Ridker PM, Hunter DJ, Willett WC, Rimm EB, Chasman DI, Hu FB, & Qi L (2012). Sugar-Sweetened Beverages and Genetic Risk of Obesity. The New England journal of medicine PMID: 22998338
  4. Caprio S (2012). Calories from Soft Drinks – Do They Matter? The New England journal of medicine PMID: 22998341
  5. Changes to the protocol http://clinicaltrials.gov/archive/NCT00893529/2011_02_24/changes
  6. Overweight and Obesity: Childhood obesity facts  and A growing problem (www.cdc.gov)
  7. NRC Wim Köhler Eén kilo lichter.NRC | Zaterdag 22-09-2012 (http://archief.nrc.nl/)
  8.  The Best Study Design… For Dummies (https://laikaspoetnik.wordpress.com)
  9. Studies point to sugary drinks as culprits in childhood obesity – CTV News (ctvnews.ca)
  10. Hans van Maanen. Suiker uit fris, De Volkskrant, 29 september 2012 (freely accessible at http://www.vanmaanen.org/)
  11. Sugar-Sweetened Beverages, Diet Coke & Health. Part I. (https://laikaspoetnik.wordpress.com)
  12. Roni Caryn Rabina. Avoiding Sugared Drinks Limits Weight Gain in Two Studies. New York Times, September 21, 2012




Silly Sunday #43 Know Your Numbers

20 11 2011

As I touched upon in Grand Rounds 8.5 the Mayo Clinic Center held the 3rd Social Media’s Health Care Social Media Summit a few weeks ago. Lots of good information and resources were shared, including the video below. The video has already gone viral (it has been viewed appr. 24,000 times), but most important is that its message gets viral.

The song is a parody of 867-5309/Jenny, produced by the Mayo Clinic Center* to promote healthy heart awareness, especially among women:

Heart disease is the number one killer of men and women, but most women aren’t aware of this.

You need to know your numbers, don’t let them get too highblood pressure, lipids and BMI

I love it & remember, know your numbers!

Go to http://knowyournumbers.me/ to calculate your heart risk (BMI and LDL-cholesterol) and see how you can lower it.

You can become a fan of Mayo Clinic at Facebook:
http://www.facebook.com/MayoClinic

* For this purpose, the band of Ron Menaker, the administrator for the Mayo Clinic Division of Cardiovascular Diseases, was renamed to “Tommy and the Heartbeats” (see The  Making of  Know Your Numbers) .

Hattip: Scott Hensley (Facebook)





The Second #TwitJC Twitter Journal Club

14 06 2011

In the previous post I wrote about  a new initiative on Twitter, the Twitter Journal Club (hashtag #TwitJC). Here, I shared some constructive criticism. The Twitter Journal Club is clearly an original and admirable initiative, that gained a lot of interest. But there is some room for improvement.

I raised two issues: 1. discussions with 100 people are not easy to follow on Twitter, and 2. walking through a checklist for critical appraisals is not the most interesting to do (particularly because it had already been done).

But as one of the organizers explained, the first session was just meant for promoting #twitjc. Instead of the expected 6 people, 100 tweople showed up.

In the second session, last Sunday evening, the organizers followed a different structure.

Thus, I thought it would only be fair, to share my experiences with the second session as well. This time I managed to follow it from start to finish.

Don’t worry. Discussing the journal club won’t be a regular item. I will leave the organization up to the organizers. The sessions might inspire me, though, to write a blog post on the topic now and then. But that may only work synergistic. (at least for me, because it forces me to rethink it all)

This time the discussion was about Rose’s Prevention Paradox (PDF), a 30 year old paper that is still relevant. The paper is more of an opinion piece, therefore the discussion focused on the implications of the Prevention Paradox theory. It was really helpful that Fi wrote an introduction to the paper, and a Points of Discussion beforehand. There were 5 questions (and many sub-questions).

I still found it very hard to follow it all at Twitter, as illustrated by the following tweet:

  • laikas I think I lost track. Which question are we? #twitjc Sun Jun 12 20:07:03
  • laikas @MsPhelps ik werd wel helemaal duizelig van al die tweets. Er zijn toch wel veel mensen die steeds een andere vraag stellen voor de 1e is beantwoord -9:47 PM Jun 12th, 2011 (about instant nausea when seeing tweets rolling by and people already posing a new question before the first one is answered)

I followed the tweets at http://tweetchat.com/room/twitjc. Imagine tweets rolling by and you try to pick up those tweets you want to respond to (either bc they are very relevant, or because you disagree). By the time you have finished your tweet, already 20 -possibly very interesting tweets- passed by, including the next question by the organizers (unfortunately they didn’t use the official @twitjournalclub account for this).

Well, I suppose I am not very good at this. Partly because I’m Dutch (thus it takes longer to compose my tweets), partly because I’m not a fast thinker. I’m better at thorough analyses, at my blog for instance.

But this is Twitter.  To speak with Johan Cruyff, a legendary soccer-player from Holland, “Every disadvantage has its advantage”.

Twitter may not favor organized discussions, but on the other hand it is very engaging, thought-provoking and easy accessible. Where else do you meet 100 experts/doctors willing  to exchange thoughts about an interesting medical topic?

The tweets below are in line with/reflect my opinion on this second Twitter Journal Club (RT means retweeting/repeating the tweet):

  • laikas RT @themattmak@fidouglas @silv24 Congratulations again on a great #twitjc. Definitely more controversial and debate generating than last week’s! -9:18 PM Jun 12th, 2011
  • laikas @silv24 well i think it went well (it is probably me, I’m 2 slow). This paper is broad, evokes much discussion & many examples can B given -9:45 PM Jun 12th, 2011
  • DrDLittle Less structure to #twitJC last night but much wider debate 7:41 AM Jun 13th, 2011
  • amitns @DrDLittle It’s obviously a very complex topic, more structure would have stifled the debate. A lot of food for thought.#twitJC -7:45 AM Jun 13th, 2011

Again, the Twitter Journal Club gained a lot of interest. Scientist and teachers consider to borrow the concept. Astronomers are already preparing their first meeting on Thursday… And Nature seems to be on top of it as well, as it will interview the organizers of the medical and the astronomy journal club for an interview.

Emergency Physician Tom Young with experience in critically appraisal just summarized it nicely: (still hot from the press):

The two meetings of the journal club so far have not focussed in on this particular system; the first used a standard appraisal tool for randomised controlled trials, the second was more laissez-faire in its approach. This particular journal club is finding its feet in a new setting (that of Twitter) and will find its strongest format through trial and error. indeed, to try to manage such a phenomenon might be likened to ‘herding cats’ that often used description of trying to manage doctors, and I think, we would all agree would be highly inadvisable. Indeed, one of its strengths is that participants, or followers, will take from it what they wish, and this will be something, rather than nothing, whatever paper is discussed, even if it is only contact with another Tweeter, with similar or divergent views. 

Indeed, what I gained from these two meetings is that I met various nice and interesting people (including the organizers, @fidouglas and @silv24). Furthermore, I enjoyed the discussions, and picked up some ideas and examples that I would otherwise wouldn’t know about. The last online meeting sparked my interest in the prevention paradox. Before the meeting, I only read the paper at a glance. After the session I decided to read it again, and in more detail. As a matter of fact I feel inspired to write a blog post about this theory. Originally I planned to write a summary here, but probably the post is getting too long. Thus I will await the summary by the organizers and see if I have time to discuss it as well.

Related articles





Health Care Reform 2010- Obama, USA, Bill, Dutch, Plan, Doctors, Letterman, Pills, $ & other Random Thoughts

30 03 2010

“I do believe the only way we can end all preventable deaths and the suffering of millions is to provide decent health care to all.”
Hilary Benn, 2006
———————

The next Grand Rounds will be hosted by Evan Falchuk at SEE FIRST (Insights into the Uncertain World of Healthcare).  Evan’s theme is Health Care Reform.

How will it affect your life, your medical practice, your experience as a patient, as an insured, an employer, an employee, someone without insurance?  What are your reactions to the politics, and what do you think will happen next?  I’m asking for your candid views on health care reform seen from whatever perspective you bring.  Medicine, politics, business, humor, left, right, center, up, down, you name it.

Health Care Reform has been a theme more than once in this Grand Rounds, i.e. February 10th at the Health Care Blog, and at Obama’s inauguration day (Ten Suggestions For Healthcare Reform) by Val Jones, MD.

The question is which health care reform? Because after all, this is an international Grand Round with bloggers from the US, Europe, Africa, Australia & Asia.
Probably, just as Google.nl (Dutch) already suggests the theme is meant to be about the USA health care bill of Obama, the future plan, and its costs (see Google Fig).

Since I’m from the Netherlands my non-US readers probably need an introduction first:

Recently  the Patient Protection and Affordable Care Act (known as the “Senate bill”) became law on March 23, 2010 and was shortly thereafter amended by the Health Care and Education Reconciliation Act of 2010 and passed by both houses on March 25 without any support from republicans (source: Wikipedia).  Please see Reuters and CNN for an overview of the March 2010 reforms and the year in which they take effect  and the New York Times [1] for the effect per types of household (i.e. Fig. at the right)

The legislation will tighten regulation of insurance companies and is expected to extend medical coverage to more than 30 million uninsured Americans. As explained by Barack Obama in the CNN-video [2] below, it will take 4 years to implement fully may of these reforms, but some desperately needed reforms will take effect right away.  For instance, having a child with a pre-existing medical condition will no longer be the basis for denial of coverage or higher premiums in the old system.


more about “Health Care:What happens when”, posted with vodpod

As a Dutch citizen, I simply can’t imagine that an insurance would be refused because my girl has asthma and I would to have pay a lot more because I happen to have a chronic disease. I can’t imagine that so many people (from a rich country) are uninsured.

As of January 2006 Our Dutch Health Care has been reformed as well. (Officially) there is no longer a fragmented system with compulsory social insurance for the majority and private health care insurance for people with a higher income. Now there is a standard insurance for all, where the insurers have to accept all patients, with no difference in premium, and no surcharges. Children up to the age of 18 years are insured for free.
Both employer and  government will contribute to the Health Insurance fund, and the insured will pay a nominal premium for their standard insurance directly to the health insurer. People with a low income can apply for a care allowance.
To avoid that health insurers seek to avoid less healthy clients, insurers are entitled to compensation for expensive customers. Although not as ideal as conveyed by the Dutch Government in their commercial-like video [3] (a too central role for the insurers, considerably less covered by the basic health insurance) it still is a pretty good and affordable health care system.

more about “MinVWS | The new health care system i…“, posted with vodpod [press T for English translation]

It is often difficult to imagine how things work in another country unless you’ve been there or hear it through somebody else.

A Dutch correspondent in the US, Tom-Jan Meeus wrote a eye-opening article in the Dutch NRC newspaper [4] about the US health care.

When Meeus collected his first prescriptions from a US pharmacy, he had to pay six times as much for the same pills (same brand, logo, packing) as in the Netherlands. And he was even more surprised that the prices were negotiable. But he got used to the US health care system: he gets an expensive check-up each 2 months instead of the once yearly (when needed) doctor visit back in Holland. In this way his doctor safeguards himself against health insurance claims. Furthermore, his doctor “has to keep the pot boiling too”.
This man knows many influential people and has valuable inside information, i.e. about the health status (botox, psychoses) of some of the key players in the health care system. In addition, he was one of the doctors who thwarted Clintons Health Reform: his glory years. This friendly conservative doctor wants freedom of choice, for himself and his patients. When Meeus objects that this freedom of choice becomes a little expensive, the doctor argues that top health care costs a little (US doctors know they are “the best in the world”)  and continues: “do you really think the health care becomes any cheaper when Obama subsidizes 30 million people to get insured? Hanky Panky, that is what it is.” But he knows a way to circumvent the rules. He cut the ties with two insurance companies that reimburse too little. “Perhaps, we can’t stop Obama, but we can undermine him. Why should we help people when we don’t make money out of it…”.

Hopefully not all the doctors think this way (I’m sure the blogging doctors that I know, don’t), but lets give a moments thought to two statements: That the US Healthcare is “the best” (as it is) and that the new health care system costs too much.

We first have to find out whether the money was well spend before the health care renewal.

I’ve shown the figures before (see [5] and [6]), but here are some other representations.

1. According to the Organization for Economic Cooperation and Development (OECD), the US spent 15.3 percent of its GDP on health care in 2006 and this number is rising. As you can see this is far more than the other countries spend.

This trend was already visible in the early eighties: the last 10-20 years the US spend far more money on health care than other rich countries..


And although the U.S. Medicare coverage of prescription drugs began in 2006, most patented prescription drugs are more costly in the U.S. than in most other countries. Factors involved are the absence of government price controls (Wikipedia).

Perhaps, surprisingly, the higher health expenditure hasn’t lead o a higher life expectancy. (78 years in the US versus 82 years in Japan in 2007). The differences are huge if one plots health spending per capita against life expectancy at birth.

Just like the international comparison, higher health care expenditures in different parts of America don’t result in a better health care for all this extra spending. Miami spends 3 times as much money per person health care than Salem (Oregon). Many doctors in Miami, for instance, perform a bunch of tests, like ECG’s, after chest complaints, because they have the necessary devices, not because all these tests have proven useful. Despite all expensive tests and treatments, Miami (and comparable great spenders)  has the worst death rate following a heart attack.* [ source, video in ref 5 and the Organisation for Economic Co-operation and Development's Health Data 2009 site.]

And this is how the US health care works:  simply more treatments and tests are available, but the incentives are wrong: physicians are paid for the quantity of care not the quality.

Just like the doctor of Tom-Jan Meeus, who did a two-monthly unnecessary check-up.

Or as the internist Lisa Bernstein suggests in the New York Times [7]:

For instance, if an asymptomatic, otherwise healthy, patient comes to me wanting a whole-body CT scan to make sure they do not have something bad hiding inside of them, I would decline and educate him or her that there is no data to show that this test has any significant benefit to offset the potential radiation or other harm and the major medical societies do not recommend this test.”

Mind you this is the situation before the current health care reform.

But there is another thing not yet addressed: the expectations of the US-citizens. Americans (and more and more Europeans too) want those check-ups and screenings, because it gives them a (false) feeling of security and because they feel they have the right. That is why it is so difficult for people to give up unnecessary CT-scans, PSA-screening and mammograms.

One reason why Americans have a higher risk for certain diseases (diabetes, overweight, cardiovascular diseases) might be their lifestyle. And lifestyle is something you can change to a certain extent and can have great effects on your health. Lifestyle is also something you can learn. You can learn to enjoy good food, you can avoid the 3 times daily coca cola  and it can be fun to do some exercise or for children to play outside. But still some people rather have a pill to stay healthy or  undergo all kind of (poor performing) tests to see how they’re doing.

Am I exaggerating?

No. This is reality. A few days ago. I saw Letterman in his show [8] telling Jamie Oliver (on his crusade to change the US diet habits) that “he believed diet pills were the only successful way to lose weight in the U.S. and that he expected humans to ‘evolve to the point where 1,000 years from now we all weigh 500-600lbs and it will be OK’ and that “If you would go to doctor they would be happy to give you as many pills as you need and you weight 80 pounds”

Do I fail to see Lettermans warped sense of humor?

Does he really belief this? And, more important, does the majority of Americans believe this?

For here is much to gain, both in health and health care costs.

* As far as I can tell these are only associations; other possible reasons are not taken into consideration: busy live in a metropolis or the population composition might also play a role.

Main References (all accessed 29 March 2010)

  1. NY-Times (2010/03/24) How Different Types of People Will Be Affected by the Health Care Overhaul.
  2. CNN.com (2010/03/23) Health care timeline (including video)
  3. Ministerie van VWS: The new health care system in the Netherlands
  4. NRC (2010/03/20) Tom-Jan Meeus: Mijn dokter won ook van Clinton (Dutch; subscription required).
  5. Laika’s MedLibLog (2009/09/10) Visualization of  paradoxes behind US Health Care.
  6. Laika’s MedLibLog (2009/09/25) Friday Foolery [4]: Maps & Mapping.
  7. NY Times.com (2010/03/27) health/27patient.html?src=twt&twt=nytimeshealth.
  8. The dail Mail UK (Last updated 210-03-25). Simon Cable. Don’t cry Jamie! Now David Letterman lectures Oliver and says his healthy eating crusade won’t work in America

Photo Credits

This map shows the ability of the health service of each territory to provide good basic health care to a number of people. The health service quality score for 1997 was applied to the population. The world average score for health service quality was 72 out of 100. This means that the equivalent of 4.5 billion people had access to good basic health care.The populations with the poorest health care provision live in Sierra Leone and the Central African Republic. The Sierra Leonean health system scored 36 out of 100 – that is half the world average score. Note that only the most basic care is measured here.
“I do believe the only way we can end all preventable deaths and the suffering of millions is to provide decent health care to all.” Hilary Benn, 2006 Territory size shows the proportion of people worldwide who receive good basic health care that live there.




#NotSoFunny #16 – Ridiculing RCTs & EBM

1 02 2010

I remember it well. As a young researcher I presented my findings in one of my first talks, at the end of which the chair killed my work with a remark, that made the whole room of scientists laugh, but was really beside the point. My supervisor, a truly original and very wise scientist, suppressed his anger. Afterwards, he said: “it is very easy ridiculing something that isn’t a mainstream thought. It’s the argument that counts. We will prove that we are right.” …And we did.

This was not my only encounter with scientists who try to win the debate by making fun of a theory, a finding or …people. But it is not only the witty scientist who is to *blame*, it is also the uncritical audience that just swallows it.

I have similar feelings with some journal articles or blog posts that try to ridicule EBM – or any other theory or approach. Funny, perhaps, but often misunderstood and misused by “the audience”.

Take for instance the well known spoof article in the BMJ:

“Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials”

It is one of those Christmas spoof articles in the BMJ, meant to inject some medical humor into the normally serious scientific literature. The spoof parachute article pretends to be a Systematic Review of RCT’s  investigating if parachutes can prevent death and major trauma. Of course, no such trial has been done or will be done: dropping people at random with and without a parachute to proof that you better jump out of a plane with a parachute.

I found the article only mildly amusing. It is so unrealistic, that it becomes absurd. Not that I don’t enjoy absurdities at times, but  absurdities should not assume a live of their own.  In this way it doesn’t evoke a true discussion, but only worsens the prejudice some people already have.

People keep referring to this 2003 article. Last Friday, Dr. Val (with whom I mostly agree) devoted a Friday Funny post to it at Get Better Health: “The Friday Funny: Why Evidence-Based Medicine Is Not The Whole Story”.* In 2008 the paper was also discussed by Not Totally Rad [3]. That EBM is not the whole story seems pretty obvious to me. It was never meant to be…

But lets get specific. Which assumptions about RCT’s and SR’s are wrong, twisted or put out of context? Please read the excellent comments below the article. These often put the finger on the spot.

1. EBM is cookbook medicine.
Many define EBM as “make clinical decisions based on a synthesis of the best available evidence about a treatment.” (i.e. [3]). However, EBM is not cookbook medicine.

The accepted definition of EBM  is “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients” [4]. Sacket already emphasized back in 1996:

Good doctors use both individual clinical expertise and the best available external evidence, and neither alone is enough. Without clinical expertise, practice risks becoming tyrannised by evidence, for even excellent external evidence may be inapplicable to or inappropriate for an individual patient. Without current best evidence, practice risks becoming rapidly out of date, to the detriment of patients.


2. RCT’s are required for evidence.

Although a well performed RCT provides the “best” evidence, RCT’s are often not appropriate or indicated. That is especially true for domains other than therapy. In case of prognostic questions the most appropriate study design is usually an inception cohort. A RCT for instance can’t tell whether female age is a prognostic factor for clinical pregnancy rates following IVF: there is no way to randomize for “age”, or for “BMI”. ;)

The same is true for etiologic or harm questions. In theory, the “best” answer is obtained by RCT. However RCT’s are often unethical or unnecessary. RCT’s are out of the question to address whether substance X causes cancer. Observational studies will do. Sometimes cases provide sufficient evidence. If a woman gets hepatic veno-occlusive disease after drinking loads of a herbal tea the finding of  similar cases in the literature may be sufficient to conclude that the herbal tea probably caused the disease.

Diagnostic accuracy studies also require another study design (cross-sectional study, or cohort).

But even in the case of  interventions, we can settle for less than a RCT. Evidence is not present or not, but exists on a hierarchy. RCT’s (if well performed) are the most robust, but if not available we have to rely on “lower” evidence.

BMJ Clinical Evidence even made a list of clinical questions unlikely to be answered by RCT’s. In this case Clinical Evidence searches and includes the best appropriate form of evidence.

  1. where there are good reasons to think the intervention is not likely to be beneficial or is likely to be harmful;
  2. where the outcome is very rare (e.g. a 1/10000 fatal adverse reaction);
  3. where the condition is very rare;
  4. where very long follow up is required (e.g. does drinking milk in adolescence prevent fractures in old age?);
  5. where the evidence of benefit from observational studies is overwhelming (e.g. oxygen for acute asthma attacks);
  6. when applying the evidence to real clinical situations (external validity);
  7. where current practice is very resistant to change and/or patients would not be willing to take the control or active treatment;
  8. where the unit of randomisation would have to be too large (e.g. a nationwide public health campaign); and
  9. where the condition is acute and requires immediate treatment.
    Of these, only the first case is categorical. For the rest the cut off point when an RCT is not appropriate is not precisely defined.

Informed health decisions should be based on good science rather than EBM (alone).

Dr Val [2]: “EBM has been an over-reliance on “methodolatry” - resulting in conclusions made without consideration of prior probability, laws of physics, or plain common sense. (….) Which is why Steve Novella and the Science Based Medicine team have proposed that our quest for reliable information (upon which to make informed health decisions) should be based on good science rather than EBM alone.

Methodolatry is the profane worship of the randomized clinical trial as the only valid method of investigation. This is disproved in the previous sections.

The name “Science Based Medicine” suggests that it is opposed to “Evidence Based Medicine”. At their blog David Gorski explains: “We at SBM believe that medicine based on science is the best medicine and tirelessly promote science-based medicine through discussion of the role of science and medicine.”

While this may apply to a certain extent to quack or homeopathy (the focus of SBM) there are many examples of the opposite: that science or common sense led to interventions that were ineffective or even damaging, including:

As a matter of fact many side-effects are not foreseen and few in vitro or animal experiments have led to successful new treatments.

At the end it is most relevant to the patient that “it works” (and the benefits outweigh the harms).

Furthermore EBM is not -or should not be- without consideration of prior probability, laws of physics, or plain common sense. To me SBM and EBM are not mutually exclusive.

Why the example is bullshit unfair and unrealistic

I’ll leave it to the following comments (and yes the choice is biased) [1]

Nibu A George,Scientist :

First of all generalizing such reports of some selected cases and making it a universal truth is unhealthy and challenging the entire scientific community. Secondly, the comparing the parachute scenario with a pure medical situation is unacceptable since the parachute jump is rather a physical situation and it become a medical situation only if the jump caused any physical harm to the person involved.

Richard A. Davidson, MD,MPH:

This weak attempt at humor unfortunately reinforces one of the major negative stereotypes about EBM….that RCT’s are required for evidence, and that observational studies are worthless. If only 10% of the therapies that are paraded in front of us by journals were as effective as parachutes, we would have much less need for EBM. The efficacy of most of our current therapies are only mildly successful. In fact, many therapies can provide only a 25% or less therapeutic improvement. If parachutes were that effective, nobody would use them.
While it’s easy enough to just chalk this one up to the cliche of the cantankerous British clinician, it shows a tremendous lack of insight about what EBM is and does. Even worse, it’s just not funny.

Aviel Roy-Shapira, Senior Staff Surgeon

Smith and Pell succeeded in amusing me, but I think their spoof reflects a common misconception about evidence based medicine. All too many practitioners equate EBM with randomized controlled trials, and metaanalyses.
EBM is about what is accepted as evidence, not about how the evidence is obtained. For example, an RCT which shows that a given drug lowers blood pressure in patients with mild hypertension, however well designed and executed, is not acceptable as a basis for treatment decisions. One has to show that the drug actually lowers the incidence of strokes and heart attacks.
RCT’s are needed only when the outcome is not obvious. If most people who fall from airplanes without a parachute die, this is good enough. There is plenty of evidence for that.

EBM is about using outcome data for making therapeutic decisions. That data can come from RCTs but also from observation

Lee A. Green, Associate Professor

EBM is not RCTs. That’s probably worth repeating several times, because so often both EBM’s detractors and some of its advocates just don’t get it. Evidence is not binary, present or not, but exists on a heirarchy (Guyatt & Rennie, 2001). (….)
The methods and rigor of EBM are nothing more or less than ways of correcting for our
imperfect perceptions of our experiences. We prefer, cognitively, to perceive causal connections. We even perceive such connections where they do not exist, and we do so reliably and reproducibly under well-known sets of circumstances. RCTs aren’t holy writ, they’re simply a tool for filtering out our natural human biases in judgment and causal attribution. Whether it’s necessary to use that tool depends upon the likelihood of such bias occurring.

Scott D Ramsey, Associate Professor

Parachutes may be a no-brainer, but this article is brainless.

Unfortunately, there are few if any parallels to parachutes in health care. The danger with this type of article is that it can lead to labeling certain medical technologies as “parachutes” when in fact they are not. I’ve already seen this exact analogy used for a recent medical technology (lung volume reduction surgery for severe emphysema). In uncontrolled studies, it quite literally looked like everyone who didn’t die got better. When a high quality randomized controlled trial was done, the treatment turned out to have significant morbidity and mortality and a much more modest benefit than was originally hypothesized.

Timothy R. Church, Professor

On one level, this is a funny article. I chuckled when I first read it. On reflection, however, I thought “Well, maybe not,” because a lot of people have died based on physicians’ arrogance about their ability to judge the efficacy of a treatment based on theory and uncontrolled observation.

Several high profile medical procedures that were “obviously” effective have been shown by randomized trials to be (oops) killing people when compared to placebo. For starters to a long list of such failed therapies, look at antiarrhythmics for post-MI arrhythmias, prophylaxis for T. gondii in HIV infection, and endarterectomy for carotid stenosis; all were proven to be harmful rather than helpful in randomized trials, and in the face of widespread opposition to even testing them against no treatment. In theory they “had to work.” But didn’t.

But what the heck, let’s play along. Suppose we had never seen a parachute before. Someone proposes one and we agree it’s a good idea, but how to test it out? Human trials sound good. But what’s the question? It is not, as the author would have you believe, whether to jump out of the plane without a parachute or with one, but rather stay in the plane or jump with a parachute. No one was voluntarily jumping out of planes prior to the invention of the parachute, so it wasn’t to prevent a health threat, but rather to facilitate a rapid exit from a nonviable plane.

Another weakness in this straw-man argument is that the physics of the parachute are clear and experimentally verifiable without involving humans, but I don’t think the authors would ever suggest that human physiology and pathology in the face of medication, radiation, or surgical intervention is ever quite as clear and predictable, or that non-human experience (whether observational or experimental) would ever suffice.

The author offers as an alternative to evidence-based methods the “common sense” method, which is really the “trust me, I’m a doctor” method. That’s not worked out so well in many high profile cases (see above, plus note the recent finding that expensive, profitable angioplasty and coronary artery by-pass grafts are no better than simple medical treatment of arteriosclerosis). And these are just the ones for which careful scientists have been able to do randomized trials. Most of our accepted therapies never have been subjected to such scrutiny, but it is breathtaking how frequently such scrutiny reveals problems.

Thanks, but I’ll stick with scientifically proven remedies.

parachute experiments without humans

* on the same day as I posted Friday Foolery #15: The Man who pioneered the RCT. What a coincidence.

** Don’t forget to read the comments to the article. They are often excellent.

Photo Credits

ReferencesResearchBlogging.org

  1. Smith, G. (2003). Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials BMJ, 327 (7429), 1459-1461 DOI: 10.1136/bmj.327.7429.1459
  2. The Friday Funny: Why Evidence-Based Medicine Is Not The Whole Story”. (getbetterhealth.com) [2010.01.29]
  3. Call for randomized clinical trials of Parachutes (nottotallyrad.blogspot.com) [08-2008]
  4. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, & Richardson WS (1996). Evidence based medicine: what it is and what it isn’t. BMJ (Clinical research ed.), 312 (7023), 71-2 PMID: 8555924
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are very well edged off




Screening Can’t Hurt, Can it?

23 11 2009

The next Grand Rounds is hosted by How To Cope With Pain and, not surprisingly, the main theme will therefore be pain. Now, I had a personal story in mind on the downside of testing, but I didn’t have a good title that fit the theme. Till, this Saturday when I a saw a perfect headline in the Los Angeles Times (Nov 21th), reading:

Cancer screening: What could it hurt? A lot, actually

It is a very thoughtful article showing the downside of screening. It was prompted by “the furor over this week’s recommendation from the U.S. Preventive Services Task Force that most women wait until age 50 to start routine mammograms, and then get them only every other year.” (also see kaleidoscope 2009- wk47).

They started their article as follows:

It seemed like a good idea at the time.

In 1984, Japan began screening the urine of 6-month-old infants for neuroblastoma, the most common type of solid tumor in young children. The test was simple and could show signs of cancer long before clinical symptoms arose.

Hundreds of infants went through the ordeal of diagnosis and treatment, but it didn’t reduce the number of tumors, including deadly ones, found later. Almost none of the tumors caught by screening turned out to be dangerous — and more of the screened children died from complications of surgery and chemotherapy than from the cancer itself.

In 2004, health officials ended the program.

The article further describes the potential downsides of current cancer screening protocols, including breast cancer screening.

  • But finding cancers that respond to early treatment is only one of the potential outcomes from a screening test. Many tests produce false positives, prompting additional tests that can be invasive, expensive, time-consuming and anxiety-inducing.(……)
  • Other screening tests produce false negatives, giving patients and their doctors the incorrect impression that they have nothing to worry about.
  • Some detect aggressive cancers whose outcomes aren’t improved by early detection.
  • And some identify small cancers that grow so slowly they’d never compromise a patient’s health. Many would even go away on their own.

All true but the problem is that people see it as their right to be screened (Will Women in Their 40s Be Denied etc). Cancer survivors are furious about the new breast cancer screening guidelines, they think decisions are made on political grounds and/or fear Medicare will no longer cover screening at younger age.

Why people are upset about the softened screening recommendations is because cancer is a frightening and deadly disease and because (as the Los Angeles Times explains so well) it’s easy to identify cancer survivors whose tumors were caught by screening, but it’s nearly impossible to put a face on the woman or man who is hurt by over-screening.

The first time I heard about the downside of screening was in 2004, when I attended a meeting for  Conn patients  to write an article for the patients association NVACP (see page 11-16, Dutch). Prof. Kievit, a surgeon and professor in decision analysis said:

“Imaging techniques (CT-scan or MRI) should only be applied if the stature test is positive and the aldosterone blood levels proven to be abnormally high. This is important because people often have benign nodules. Innocent nodules (incidentalomas) can obscure the diagnosis, worry the patient or even lead to unnecessary interventions. Furthermore it is inefficient to randomly subject people to all kind of tests. And please do not follow the current US trend to ask a CT-scan for your birthday!

That the balance of harm and benefit of diagnostic tests and screening can dip the wrong way can be best understood when you experience it yourself.

from: Wikipedia

During my last pregnancy my daughter was diagnosed with a mild prenatal  hydronephrosis during routine pregnancy ultrasound. Hydronephrosis is distension and dilation of the renal pelvis, usually caused by obstruction of the free flow of urine from the kidney. Since this can lead to progressive atrophy of the kidney, my little girl also had to undergo several tests to check the function of the kidneys and the cause of this anomaly. For one of those tests she had to be injected with radioactive isotopes in the catacombs of another hospital. But everything seemed o.k.: the anatomy (no obstruction) and the kidney functions. It should also be stressed that the dilatation was near-normal and didn’t worsen. Nonetheless, because of complications often seen with children with severe dilatation my daughter had to take daily antibiotics as a preventive measure. We had to regularly visit the polyclinics for an ultrasound and urine testing (to exclude infection and resistance). After a year it was decided to discontinue the antibiotic treatment. Follow-up was not needed.  Later a pediatric urologist told us that the guidelines had been changed: preventive antibiotic treatment was no longer required in case of mild hydronephrosis with no underlying cause.

My daughter developed asthma at the age of 7. Both she and her sister had atopic eczema, a known predicting factor for asthma, when they were toddlers. In line with the hygiene-theory, that states that a lack of early childhood exposure to infectious agents, increases susceptibility to allergic diseases, I often wondered whether 1 year daily antibiotic treatment wasn’t the final trigger for my daughter’s asthma. Indeed @Allergy (Ves Dimov) recently twittered about a study in J Allergy Clin Immunol that showed an association between antibiotic use in the first year of life and current symptoms of asthma in children 6 and 7 years old. A  Systematic Review of observational studies came to the same conclusion: “Exposure to at least one course of antibiotics in the first year of life appears to be a risk factor for the development of childhood asthma.” These studies had some limitations, and don’t  prove there is a causal relationship between antibiotic treatment and asthma, but they do fuel my suspicion.

In any case, although prenatal diagnosis of hydronephrosis may help to prevent later development of serious kidney disease in children with real malformations, it only resulted in “harm” in our case. Unnecessary testing (all results negative), unnecessary polyclinic visits, worries (that stayed until she was 9, when we visited the pediatric urologist to exclude an UTI, because you never know..)), unnecessary antibiotic treatment and -perhaps- the triggering of asthma. Looking back, and knowing what I know now, I wished the somewhat dilated renal pelvis had never been observed.

Last Friday I was at a lottery offered by my Sports Club. The last 2 prices were mystery prices: A total body scan of 1000 Euros each. I heard a lot of “Aaahs” and “Oooohs”. But I whispered “not for me“. The women next to me turned their heads, looked at me perplexed with their eyes blanked. Of course it is difficult to understand why one would refuse such a price, because “if screening doesn’t help, it won’t harm either”.

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An Antibiotic Past May Save Lives at the ICU.

16 03 2009

3241003338_60b07d7aba

Respiratory tract infections acquired in the intensive care unit (ICU) are important causes of morbidity and mortality, the most significant risk factor being mechanical ventilation. It is thought that hospital pneumonia commonly originates from flora colonized in the patient’s oropharynx (the area of the throat at the back of the mouth). Therefore, reduction of respiratory tract infections has been obtained by putting patients in semirecumbent instead of supine position. Another approach is selective decontamination. There are two methods of selective decontamination, SDD and SOD.

  1. SDD, Selective Decontamination of the Digestive tract consists of the administration of topical nonabsorbable antibiotics in the oropharynx and gastrointestinal tract, often concomitant with systemic antibiotics. It aims to reduce the incidence of pneumonia in critically ill patients by diminishing colonization of the upper respiratory tract with aerobic gram-negative bacilli and yeasts, without disrupting the anaerobic flora.
  2. SOD, Selective Oropharyngeal Decontamination is application of local antibiotics in the oopharynx only.

Both approaches were first introduced in the Netherlands. Most trials suggested that SDD lowered infection rates, but lacked statistical power to demonstrate an effect on mortality. However, meta-analyses and three single-center, randomized studies, did show a survival benefit of SDD in critically ill patients. Several studies had suggested that the local variant, SOD, was also effective, but SOD was never directly compared with SDD in the same study. Because of methodological issues and concern about increasing antibiotic resistance the use of both SDD and SOD has remained controversial. Even in the Netherlands where guidelines recommended the use of SDD after a Dutch publication in the Lancet (de Jonge et al, 2003) had shown the mortality to drop with 30% in the Academic Medical Center in Amsterdam, only 25% of the emergency doctors followed the guidelines.

The present Dutch study, published in the NEJM (2009), was undertaken to determine the effects on mortality in a head to head comparison of SDD and SOD. The effectiveness of SDD and SOD was determined in a crossover study using cluster randomization in 13 Dutch ICU’s, differing in size and teaching status. Cluster randomization means that ICU’s rather than the individual patients were randomized to avoid that one treatment regimen would influence the outcome of another regimen. Crossover implies that all three treatments (SDD, SOD, standard care) were administered in a random order in all ICU’s.

A total of 5939 patients were enrolled in this large study. Patients were eligible if they were expected to be intubated for more than 48 hours or to stay in the ICU for more than 72 hours. The SDD regimen involved four days of intravenous cefotaxime along with topical application of tobramycin, colistin and amphotericin B; the SOD regimen used only the topical antibiotics. Both regimens were compared with standard care. The duration of the study was six months, and the primary end point was 28-day mortality.

Of the 5,939 patients, 1,990 received standard care, 1,904 received SOD and 2,405 received SDD. Crude mortality rates in the three groups were 27.5%, 26.6% and 26.9%, respectively. These differences are not very huge and benefit was only discernable after adjustment for covariates (age, sex, APACHE II score, intubation status, medical specialty, study site, and study period): adjusted* odds ratios for 28-day mortality were 0.86 (95% CI, 0.74 to 0.99) in the SOD group and 0.83 (95% CI, 0.72 to 0.97) in the SDD group compared with standard care. This corresponded with the needed-to-treat numbers (NNT’s) of 29 and 34 to prevent one casualty at day 28 for SDD and SOD, respectively.

The limitations of the study (acknowledged by the authors) were the absence of concealment of allocation (due to the study design it was impossible to conceal the allocation for doctors at the wards), differences at baseline between the standard care and treatment groups and a mismatch between the original analysis plan and the study design (originally specified in-hospital death was the primary end point, but this did not take into account analysis of cluster effects.)

Selective Decontamination also improved microbiological outcomes, such as carriage of gram-negative bacteria in the respiratory and intestinal tracts and ICU-acquired bacteriemia. During the study periods the prevalence rates for antibiotic-resistant gram-negative bacteria were lower in the SOD and SDD periods than during the standard-care periods.

The authors concluded that both SDD and SOD were effective compared with standard care. Given the similarity in effects on survival between the treatment groups, the SOD regimen seems preferable to the SDD regimen, becauses it minimizes the risk of antibiotic resistance which poses a major threat to patients admitted to ICU’s. It should be noted that MRSA-infections are very rare in the Netherlands and in Scandinavia. The outcome of the study might therefore be different after long term treatment and/or in regions with a high prevalence of MRSA.

References

ResearchBlogging.orgde Smet, A., Kluytmans, J., Cooper, B., Mascini, E., Benus, R., van der Werf, T., van der Hoeven, J., Pickkers, P., Bogaers-Hofman, D., van der Meer, N., Bernards, A., Kuijper, E., Joore, J., Leverstein-van Hall, M., Bindels, A., Jansz, A., Wesselink, R., de Jongh, B., Dennesen, P., van Asselt, G., te Velde, L., Frenay, I., Kaasjager, K., Bosch, F., van Iterson, M., Thijsen, S., Kluge, G., Pauw, W., de Vries, J., Kaan, J., Arends, J., Aarts, L., Sturm, P., Harinck, H., Voss, A., Uijtendaal, E., Blok, H., Thieme Groen, E., Pouw, M., Kalkman, C., & Bonten, M. (2009). Decontamination of the Digestive Tract and Oropharynx in ICU Patients New England Journal of Medicine, 360 (1), 20-31 DOI: 10.1056/NEJMoa0800394

de Jonge E, Schultz M, Spanjaard L, et al. Effects of selective decontamination of the digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet 2003;362:1011-1016 (PubMed citation)

Wim Köhler (2009) Smeren tegen infectie, NRC Handelsblad, Wetenschapsbijlage 3,4 januari (Dutch, online)

Barclay, L & Vega, C (2009) Selective Digestive, Oropharyngeal Decontamination May Reduce Intensive Care Mortality, Medscape

File, T.M., Bartlett J.G.,& Thorner, A.R. Risk factors and prevention of hospital-acquired (nosocomial); ventilator-associated; and healthcare-associated pneumonia in adults.www.uptodate)

Photo Credit (CC): http://www.flickr.com/photos/30688696@N00/3241003338/ (JomCleay)





MnSOD, Carotenoids & Prostate Cancer – “You are what you eat” depends on who you are.

22 02 2009

ResearchBlogging.orgWhen you type Cancer Food Prevention in Google you get about 9 million hits, many of them dotcom sites telling you which nutrients, pills or extracts you should take to prevent cancer. Much of this information is unreliable at least.

Although it is true that numerous observational studies (cohort and case-control) do indicate a relationship between diet and cancer incidence, it is difficult to pinpoint the exact nutrients that may be responsible for a beneficial effect. Furthermore, as explained in “The Best Study Design for Dummies” observational studies provide weaker empirical evidence than RCT’s (randomized controlled trials).

For prostate cancer observational (and preclinical) data indicate that diets high in cruciferous vegetables, soy lecithins and other phytoestrogens, vitamins E and C, lycopene, Selenium, green tea (to name a few) are associated with a lower risk of prostate cancer [1].

However, recent randomized trials did not confirm positive effects of vitamin E and C and Selenium (see previous post on the negative SELECT and the PHS II-trial) and data from the PLCO (Prostate, Lung, Colorectal, Ovarian) Trial [2] suggest that the benefit of lycopene (a powerful anti-oxidant that gives tomatoes their red color) is small and that beta-carotene, an antioxidant related to lycopene, even increases the risk for aggressive prostate cancer.

lycopene-tomato

There may be many reasons why these results discords with the many observational studies performed (3)

  • Earlier positive observational studies have less methodological rigor than (large) RCT’s. In controlled trials, the random assignment of subjects to the intervention eliminates the problems of dietary recall and controls the effects of confounding factors.
  • RCT’s test one or two nutrients in isolation and sometimes in high doses assuming that a single compound may reproduce the beneficial effects of the whole foods.
  • RCT’s are often not stratisfied, differences between individuals are often not taken into account.

That this may be important is shown in a recent study on the manganese superoxide dismutase (MnSOD) polymorfism, prostate cancer and lycopene (4)

The manganese superoxide dismutase (MnSOD) gene encodes an antioxidant enzyme (SOD2) that may protect cells from oxidative damage (which may play an important role in prostatic carcinogenesis). A polymorphism [valine (V) -> alanine (A)] of MnSOD has been recently associated with a higher risk of prostate cancer.

The present study performed by Mikhak et al was a nested case-control study in the Health Professionals Follow-up Study (HPFS) with 612 incident prostate cancer cases and 612 matched controls.

The study not only investigates the role of the MnSOD gene Ala16Val polymorphism in prostate cancer risk, but also measures its interactions with baseline plasma carotenoid concentrations.

In line with several other studies (5), no overall association between MnSOD polymorphism and prostate cancer risk was found. However, a 3-fold [95% confidence interval: 1.37-7.02] increased risk of aggressive prostate cancer was observed among men with the Ala/Ala genotype in the presence of low long-term lycopene status (P-value, test for interaction = 0.02) as compared with men with the Ala/Val+Val/Val genotypes with low long-term lycopene status. In other words when the lycopene blood level is low, the Ala/Ala genotype confers a higher risk of aggressive prostate cancer compared with individuals with the other genotypes.

These results are consistent with findings from an earlier study (6) that reported when total antioxidant status is low, the MnSOD Ala/Ala genotype may be associated with an increased risk of aggressive prostate cancer. In contrast, men with the Val allele were much less sensitive for prediagnostic plasma levels of the anti-oxidants selenium, lycopene and {alpha}-tocopherol.

Thus reasoned the other way around: the anticancer effects of supplemented lycopene and other anti-oxidants may depend on the the MnSOD genotype and the levels of both endogenous and exogenous antioxidants. Similarly, a positive effect of {alpha}-tocopherol (vitamin E) observed in earlier trials appeared to be limited to smokers and/or people with low basal levels of vitamin E (see previous post).

SOURCES

  1. E-medicine/Medscape: prostate cancer and nutrition (2008) (free e-txt)
  2. Peters U, Leitzmann MF, Chatterjee N, Wang Y, Albanes D, Gelmann EP, Friesen MD, Riboli E, Hayes RB. Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev. 2007 May;16(5):962-8. (free PDF)
  3. Byers T. What can randomized controlled trials tell us about nutrition and cancer prevention? CA Cancer J Clin. 1999 Nov-Dec;49(6):353-61. Review (free PDF)
  4. B. Mikhak, D. J. Hunter, D. Spiegelman, E. A. Platz, K. Wu, J. W. Erdman, E. Giovannucci (2008). Manganese superoxide dismutase (MnSOD) gene polymorphism, interactions with carotenoid levels and prostate cancer risk Carcinogenesis, 29 (12), 2335-2340 DOI: 10.1093/carcin/bgn212
  5. Bag A, Bag N. Target sequence polymorphism of human manganese superoxide dismutase gene and its association with cancer risk: a review.
    Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3298-305. Review. (Abstract)
  6. Li H, Kantoff PW, Giovannucci E, Leitzmann MF, Gaziano JM, Stampfer MJ, Ma J. Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinical significant prostate cancer.Cancer Res. 2005 Mar 15;65(6):2498-504.

You may also want to read:

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Huge disappointment: Selenium and Vitamin E fail to Prevent Prostate Cancer.

16 11 2008

select

October 27th the news was released that ([see here for entire announcement from nih.gov]

“an initial, independent review of study data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), funded by the National Cancer Institute (NCI) and other institutes that comprise the National Institutes of Health shows that selenium and vitamin E supplements, taken either alone or together, did not prevent prostate cancer. The data also showed two concerning trends: a small but not statistically significant increase in the number of prostate cancer cases among the over 35,000 men age 50 and older in the trial taking only vitamin E and a small, but not statistically significant increase in the number of cases of adult onset diabetes in men taking only selenium. Because this is an early analysis of the data from the study, neither of these findings proves an increased risk from the supplements and both may be due to chance.”

SELECT is the second large-scale study of chemoprevention for prostate cancer. Chemoprevention or chemoprophylaxis refers to the administration of a medication to prevent disease. The SELECT trial aimed to determine whether dietary supplementation with selenium and/or vitamin E could reduce the risk of prostate cancer among healthy men. It is a randomized, prospective, double-blind study with a 2×2 factorial design, which means that the volunteering men received either one of the supplements, b2x2-select-vierkantoth supplements or no supplements (but placebo instead), without knowing which treatment they would receive.
The trial volunteers were randomly assigned to one the following treatments:

  1. 200 µg of selenium and 400 IU of vitamin E per day. (both supplements)
  2. 200 µg of selenium per day and placebo
  3. 400 IU of vitamin E per day and placebo
  4. two different placebo’s (neither supplement)
    (µg = micrograms, IU = International Units)

Enrollment for the trial began in 2001 and ended in 2004. Supplements were to be taken for a minimum of 7 years and a maximum of 12 years. Therefore the final results were anticipated in 2013. However, but due to the negative preliminary results, SELECT participants still in the trial are now being told to stop taking the pills. The participants will continue to have their health monitored by study staff for about three more years, continue to respond to the study questionnaires, and will provide a blood sample at their five-year anniversary of joining the trial, to ensure their health and to allow a complete analysis of the study. (see SELECT Q & A).

In an interview with CBS, one of the investigators Dr Katz, said he was highly disappointed and concerned, because he had high hopes for the trial. “I”m disappointed with the study. I’m very concerned about the results of the trial.

more about “Vitamin E A Flop In Prostate Cancer T…“, (with 15 sec advertisement first) posted with vodpod. This video is derived from CBS news.

Dr. Klein, one of the principal investigators, has published as many as 14 publications on the SELECT trial (see PubMed). He has always been a strong advocate of this huge trial.

The question now is:
Was there enough evidence to support such a large trial? Could this result have been foreseen? Would the trial have had different outcomes if other conditions had been chosen?

The SELECT trial seems to add to the ever growing list of disappointing “preventive” vitamin trials. See for instance this blogpost of sandnsurf on “a systematic review of all the published randomized controlled trials (RCTs) on multivitamins and antioxidant supplements in various diseases, and their effect on overall mortality” concluding:

“Taking the antioxidant vitamins A (and its precursor beta-carotene) and E singly or in multivitamins is dangerous and should be avoided by people eating a healthy diet. On a diet like that recommended here, the intake of these and other important vitamins should be high, with no need for supplementation.”

Quite coincidentally I commented to Sandsnurf blogpost referring to the SELECT trial, 1 week before the bad outcome was announced):

Indeed, in many RCT’s vitamin supplements didn’t have the beneficial effects that they were supposed to have. Already in the early nineties, adverse effects of beta-carotene (higher mortality in smokers) have been shown in several RCT’s. Still, because vitamin E had an expected positive effect on prostate cancer in one such trial, vitamin E is now being tested together with selenium (2X2) in a very large prostate cancer trial. Quite disturbingly, 8 times higher doses vitamin E are being used (400IE) compared to the original study. If the Lawson study is right, the outcome might be harmful. Worrying.

It might be argued that it is easy to criticize a study once the outcome is known. However, this critique is not new.

Already in 2002 a very good critique was written by MA Moyad in Urology entitled: Selenium and vitamin E supplements for prostate cancer: evidence or embellishment?

Here I will summarize the most important arguments against this particular trial (largely based on the Moyad paper)

  • SELECT was based on numerous laboratory and observational studies supporting the use of these supplements. As discussed previously such study designs don’t provide the best evidence.
  • The incidence, or rate of occurrence, of prostate cancer was not the primary focus or endpoint of the few randomized controlled trials studies on which the SELECT study was based.
  • A 2×2 design is inadequate for dose-response evaluations, in other words: before you start the trial, you have to be pretty sure about the optimal dose of each supplement and of the interactive effect of vitamin E and selenium in the particular doses used. The interaction between two agents might be synergistic or additive, also with respect to any negative (i.e. pro-oxidant) effect.
  • Eight times higher vitamin E doses (400IE) have been used than in the ATCB study showing a benefit for vitamin E in decreasing prostate cancer risk! This is remarkable, given the fact that high doses of anti-oxidants can be harmful. Indeed, a prospective study has shown, that vitamin E supplements in higher doses (> or =100 IU) are associated with a higher risk of aggressive or fatal prostate cancer in nonsmokers.
  • Other forms of vitamin E and selenium have been proposed to be more effective. For instance dietary vitamin E (gamma tocopherol and/or gamma tocotrienols) might be more effective in lowering prostate cancer risk than the chemically-derived vitamin E (dl-alpha tocopherol acetate) used in SELECT. Also the used selenomethionine might be less effective than organically-bound selenium.
  • Selenium and vitamin E supplements seem to provide a benefit only for those individuals who have lower baseline plasma levels of selenium or vitamin E.
  • There may be other compounds that may be more effective, like finasteride, lycopene, statins (or with respect to food: a healthy lifestyle)

Katz said. “I would have hoped this would have been the way to prevent cancer in this country.”

Isn’t it a little bit naive to expect such huge effects (25% less prostate cancers) just by taking 2 supplements, given the thoughts summarized above?

In the interview, shown in the CBS-interview LaPook concludes “This is a major disappointment, but it is also progress. Because it’s also important to know what does not prevent cancer.”

Well I wonder whether it is ethical ànd scientifically valid, to do such a costly experiment with 35.000 healthy volunteers, based on such little evidence. Do we have to test each single possibly effective food ingredient as a single intervention?

SOURCES:
Official publications and information

- EA Klein: http://www.ncbi.nlm.nih.gov/pubmed/12756490
- Lippman SM, J Natl Cancer Inst. 2005 Jan 19;97(2):94-102. Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). (PubMed record)
- new2.gif The results of the SELECT trial are published in JAMA: Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial. Scott M. Lippman, Eric A. Klein et al SELECT)JAMA. 2008;0(2008):2008864-13, published online December 9th 2008.

- SELECT Q&A: www.cancer.gov/newscenter/pressreleases/SELECTQandA
- General information on SELECT http://www.crab.org/select/
- Information on Study design (from Cancer Gov.clinical trialsSWOG s0000) and from clinicaltrials.gov

- More information on study designs and the ATCB trial (on which this study was based) in a previous post: the best study design for dummies

NEWS
- CBS Evening News Exclusive: Vitamin E And Selenium Fail To Prevent The Disease In Large Clinical Trial, NEW YORK, Oct. 27, 2008
- Los Angelos Times; Vitamin E, selenium fail to prevent prostate
- Emaxhealth: NCI stops prostate cancer prevention trial. With many good links to further information





The (un)usefulness of regular breast exam

7 09 2008

Regular breast exam, either by women theirselves (BSE, breast self exam) or a doctor or nurse, has been promoted for many years, because this would help to detect breast cancer earlier, and “when breast cancer is found earlier, it’s easier to treat and cure” . At least that is what most people believe and what has been advocated by organizations and Internet companies (i.e. selling special gloves) (see figure).

The idea that regular breast exam is truly beneficial, however, has recently been challenged by a Cochrane Systematic Review, conducted by Kösters and Gøtzsche.[1] This review has stirred up quite a debate among doctors, guideline-makers, patients and women. Many major organizations and advocacy groups have stopped recommending routine BSE. Reactions of patients vary from ‘reluctant’ to ‘confused that it is no longer needed’ or even a bit angry (‘it is my body and I decide whether I check it or not’). See for instance these reactions: 1, 2, 3. Coverage in the media is sometimes misleading, but reactions of (some) doctors or “experts in the field” also do not always help to convey a clear message to the public either. Some seize the opportunity to rant against EBM (Evidence Based Medicine) in general, which makes things even less transparent, see for instance this post by Dr Rich (although he has some good points as well), this story in the Herald and this one in Medcape.

In a question-answer like way I try to cover the story.

1. What is the conclusion from the study?
The authors conclude that regular breast examination (BE) does more harm than good and is therefore not recommended.

2. Which harm, which good?
Breast examination didn’t lower mortality (not beneficial), whereas it led to more unnecessary biopsies (harm).

3. Why did they look at mortality only?
They didn’t, they also scored the number and stage of cancers identified. However mortality (or really survival) is an outcome that matters most for patients. Suppose the screening finds more breast cancers, but early intervention does not lead to any cure, than the early recognition of the cancer is of no real value to the patient.

4. Why are more unnecessary biopsies considered as harm?
Biopsies are an invasive procedure and lead to unnecessary anxiety, that can have a long-lasting effect on psychological well-being. Extra tests to rule out that it is not cancer also cost a lot of money. Whether it is ‘worth it’ depends on whether -and to which extent- people’s lives are saved (or quality of life improved).

5. What kind of study is it?
It is a systematic review (of controlled clinical trials) made by the Cochrane Collaboration (see glossary). Generally these systematic reviews are of high methodological quality, because of the systematic and explicit methods used to identify, select and critically appraise relevant research. After extensively searching for all trials, only controlled clinical trials (studies of the highest evidence) with predefined characteristics are included. Thus authors are really looking for all the high level evidence there is, instead of grabbing some papers from the drawer or looking at the core English language journals only.

6. Is this new information?
No, not really. In fact this systematic review is an update of a previous version, published in 2003. The studies included and the conclusions remain the same. As shown from the scheme below (taken from a figure in a very interesting opinion paper entitled “Challenges to cancer control by screening” (see abstract here), the attitude towards breast self examination already changed soon after the original trials were published.

Nature Reviews Cancer 3, 297 (2003)

M.N. Pollak and W.D. Foulkes: Nature Reviews Cancer 3, 297 (2003)

7. Omg? ….
All Cochrane Systematic have to be regularly updated to see if there isn’t any new evidence that could alter the conclusions. In this case, after updating the search, no new studies of good quality were found. However, there are still some trials ongoing.

8. Can we rely on these conclusions? Is the Cochrane Review of good enough quality?
The Cochrane Review itself is of high quality, but the two randomized studies included, one from Russia (1999: ~122,500 participants) and one from Shanghai (2002: ~266,000 participants) have some serious flaws. For instance, both studies did not have an adequate allocation concealment (keeping clinicians and participants unaware of the assignments). An inadequate concealment undermines the validity of a trial (see for instance this 2002 Lancet paper). Also, description of statistical methods was lacking. Furthermore, data from the Moscow-branch of the Russian study were incomplete (these are excluded), mammography might have been used additionally and in the Shanghai trial there was a large difference in all-cause mortality in favor of the control group, suggesting that the two groups were imbalanced from the start.

9. Can the results of these rather old trials from countries as China and Russia be directly translated to the situation in Western Countries with a high standard of care?
Intuitively I would say ‘probably not’. However, we still don’t know whether the current western quality of care would actually lead to a better outcome after early detection, because it has never be tested in a well performed controlled trial.

10. Is this outcome applicable to anyone?
No, the studies are applicable to healthy, middle-aged woman without any particular risk. Screening methods might be more useful or even required for woman at high risk (i.e. familiar predisposition, previous ovarian or breast cancer).

11. Still, in recent interviews experts in the field say they do know that BSE is beneficial. One doctor for instance referred (in this Medscape paper) to a recent trial, that concluded that breast self-examination should be promoted for early detection of breast cancer (see here).
Either these doctors/experts give their personal opinion, refer to unpublished data or to studies with a lower evidence level. For instance the study referred to by Dr. Goldstein above was a retrospective study looking at how accurately woman could detect a breast tumor. Retrospective studies are more biased (see previous post on levels of evidence for dummies). Furthermore this study didn’t evaluate a hard outcome (survival, better prognosis) and there are just as many retrospective studies that claim the opposite, i.e. this article of Newcomb et al in J Natl Cancer Inst. 1991(abstract).

12. Should woman refrain from breast self examination then?
I found a short article (half A4) in the Dutch woman’s magazine (!) Viva very clear and concise.
Four woman gave their opinion.

A patient who had had a previous breast tumor kept on checking it (high risk group).

The director of a patient association said: “there is no evidence that BSE is beneficial: don’t feel quilty if you don’t check your breasts. But it might have a reassuring effect if you do”.
The spokeswoman of the Dutch association “struggle against cancer” (KWF) said that they didn’t promote structural breast exam any longer, but they advised to “know your body” and know the alarm signals (retracting nipple etc), much the same way as you check for alterations in nevi. Most woman find small alterations anyway, said another, for instance when taking a shower.
Indeed, exemplified by my own experience: 18 years ago my mother detected breast cancer when feeling a lump in her breast under the shower (malignant, but curable).

The Cochrane authors are also very clear in their review about the necessity of women noticing changes to their breast.

“Some women will continue with breast self-examination or will wish to be taught the technique. We suggest that the lack of supporting evidence from the two major studies should be discussed with these women to enable them to make an informed decision.
It would be wrong, however, to conclude that women need not be aware of any breast changes. It is possible that increased breast awareness may have contributed to the decrease in mortality from breast cancer that has been noted in some countries. Women should, therefore, be encouraged to seek medical advice if they detect any change in their breasts that may be breast cancer.”

Listen to this Podcast featuring the Cochrane authors to learn more about their findings

Download:

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Periodieke borstcontrole, uitgevoerd door vrouwen zelf of door artsen/verplegers, is jarenlang gepromoot, omdat je hierdoor eerder borstkanker zou ontdekken, waardoor het beter te genezen is. Deze gedachte wordt actief uitgedragen door verschillende organisaties en Internetbedrijven (die bijvoorbeeld speciale handschoenen verkopen, zie figuur).

Dat regelmatige borstcontrole zinvol zou zijn, wordt echter tegengesproken door een recent Cochrane Systematisch Review, uitgevoerd door Kösters and Gøtzsche.[1] Dit review heeft heel wat losgemaakt bij dokters, makers van richtlijnen, patienten en vrouwen in het algemeen. Veel belangrijke organisaties bevelen niet langer het maandelijks controleren van de borsten aan. De reacties van (engelstalige) patienten varieert van ‘opgelucht’ tot ‘in verwarring gebracht’ of lichtelijk boos (‘ik maak verdorie zelf nog wel even uit wat ik doe’). Zie bijv. enige reacties hier: 1, 2, 3. De berichtgeving door sommige media is soms misleidend. Dat is vaker zo, maar vervelender is het dat reacties van sommige artsen of ‘experts’ heel gekleurd zijn, waardoor de boodschap niet goed overkomt bij het publiek. Sommigen grijpen de gelegenheid aan om even goed op EBM (Evidence Based Medicine) af te geven, zie bijv. deze post van Dr Rich (die overigens ook zinnige dingen opmerkt), dit bericht in de Herald and dit in Medcape (zie onder).

Ik zal proberen om dit onderwerp in een vraag-en antwoord-vorm te bespreken.

1. Wat zijn de conclusies uit de studie?
Dat structureel borstonderzoek door vrouwen zelf of door artsen/verplegers meer kwaad dan goed doet, en dus niet langer aanbevolen kan worden.

2. Welk kwaad, welk goed?
Maandelijkse controle van de borsten leidt niet tot minder sterfte (niet ‘beter’), maar wel tot 2x zoveel biopsies (kwaad, ‘harm’).

3. Waarom kijken ze alleen naar sterfte?
Ze keken ook naar het aantal ontdekte kankers en hun stadia, maar sterfte (of eigenlijk overleving) is veel belangrijker voor de patient. Stel dàt je eerder borstkanker vindt door screening, maar dit leidt niet tot genezing en/of een betere kwaliteit van leven, dan schiet de patient daar niets mee op, integendeel (zij weet het langer).

4. Waarom worden biopsies als ‘schadelijk’ gezien?
Een biopsie is een medische ingreep, die -zeker in het geval van vermoede kanker-, een langdurig negatief kan effect hebben op iemand’s psychische gesteldheid. Biopsies en andere testen, die nodig
zijn om kanker uit te sluiten kosten veel geld. Of dit het ‘waard’ is hangt af van hoe nuttig die testen werkelijk zijn, dus of ze de kans op overleving of een betere kwaliteit van leven verhogen.

5. Wat voor een studie is het?
Het is een systematisch review (van “gecontrolleerde” klinische studies), gemaakt door auteurs van de Cochrane Collaboration (zie Glossary). Over het algemeen zijn deze reviews van uitstekende methodologische kwaliteit, omdat studies volgens een vast stramien gezocht, geselecteerd, beoordeeld en samengevat worden. Van te voren worden alle criteria vastgelegd. Dus de auteurs proberen echt alle evidence (positief of negatief, zonder taalbeperking) boven water te krijgen in plaats van wat artikelen uit de kast te trekken of alleen maar de top-tijdschriften te selecteren.

6. Is deze informatie nieuw?
Nee, niet echt. Dit systematische review is in feite een update van een vorige versie uit 2003. De geincludeerde studies en de conclusies zijn hetzelfde. Zoals te zien in het schema hieronder (Nature Reviews Cancer 2003, samenvatting hier), is de houding ten opzichte van borstzelfcontrole al sinds de publicaties van de oorspronkelijke studies (die in het Cochrane Review opgenomen zijn) veranderd. De Amerikaanse Cancer Society beveelt bijvoorbeeld al sindsdien maandelijks zelfonderzoek niet meer aan.

Nature Reviews Cancer 3, 297 (2003)

M.N. Pollak et al: Nature Reviews Cancer 3, 297 (2003)

7. Huh? ….
Alle Cochrane Systematische Reviews behoren regelmatig ge-update te worden om te kijken of er geen nieuwe evidence is die tot een andere conclusie leidt. In dit geval werden er geen nieuwe studies van goede kwaliteit gevonden. Wel lopen er nog enkele studies.

8. Kunnen we van deze conclusies op aan? Zijn Cochrane Reviews van een voldoende kwaliteit?
Het Cochrane Review zelf is van een goede kwaliteit, maar op de 2 studies die opgenomen zijn in het review (een uit Rusland uit 1999 met ca. 122.500 deelnemers en een uit Shanghai uit 2002 met ca. 266.000 deelnemers) is wel het een en het ander aan te merken. In beide studies was de blindering van de patienten en de behandelaars voor de toewijzing van de behandeling (concealment of allocation) onvoldoende. Daarmee wordt zo’n studie minder valide (zie bijv. dit artikel uit de Lancet van 2002). Verder was de beschrijving van de statistische methoden onvolledig, waren gegevens van de Moskouse tak van de studie Russische studie niet compleet (zijn wel uitgesloten) , en was er in de Shanghai studie een groot verschil in algehele sterfte (dus niet alleen borstkanker), wat een duidelijke aanwijzing is dat de 2 groepen al vanaf het begin niet gelijkwaardig waren.

9. Zijn de resultaten uit deze oudere studies uit landen als China en Rusland zondermeer op Westerse landen van toepassing?
Intuitief zou ik zeggen van niet. De zorg in Westerse landen en de hedendaagse behandelingen zijn mogelijk beter. Alleen weten we niet of screening door zelfonderzoek hier wel tot een betere uitkomst zou leiden, omdat dat nooit in goede gecontroleerde studies is bestudeerd.

10. Gelden de conclusies voor alle vrouwen?
Nee, de studies zijn allen gedaan -en daarom alleen van toepassing op gezonde vrouwen van zo’n 35 tot 65 jaar. Screeningsmethoden, waaronder borstzelfonderzoek, zijn wel aan te bevelen voor vrouwen, die tot de risicogroep behoren (vrouwen die erfelijk belast zijn of die eerder al borst- of eierstokkanker hebben gehad).

11. Toch stellen bepaalde deskundigen dat zelfonderzoek wel gunstig is. Een dokter (Dr. Goldstein) verwees daarbij in een interview in Medscape (zie hier) naar een heel recente studie (zie hier).
Deze artsen/deskundigen geven hun persoonlijke mening, verwijzen naar niet-gepubliceerde studies of naar studies met een lagere bewijskracht. De studie waar Dr. Goldstein naar verwijst is bijvoorbeeld een retrospectieve studie, die alleen onderzoekt hoe goed vrouwen borstkanker kunnen vaststellen. Retrospectieve studies hebben altijd meer vertekening (zie een vorig bericht over het beste studietype… voor dummies). Verder keek deze studie niet naar harde uitkomsten (overleving, betere prognose). Daarnaast zijn er evengoed retrospectieve studies die het tegenovergestelde beweren, zie bijvoorbeeld dit artikel van Newcomb PA et al in J Natl Cancer Inst. 1991(abstract).

http://breastselfexam.ca/section1slide2.html

12. Moeten vrouwen dan helemaal geen borstcontrole meer doen?
Ik kwam toevallig ergens op een terrasje een klein stukje in de Viva (1-7 aug 2008) tegen dat ik heel duidelijk vond.
4 Vrouwen gaven hun mening.

Een vrouw die eerder borstkanker had gehad bleef maandelijks controleren (risicogroep).
De directeur van de Borstkankervereniging zei: “Wetenschappelijk is aangetoond dat borstcontrole niet zorgt voor minder sterfte door borstkanker. Voel je niet schuldig als je het niet doet. Doe je het wel om zo je borsten goed te leren kennen, dan heeft dat vooral een psychologisch effect”. De woordvoerdster van de KWF Kankerbestrijding zei dat ze periodieke zelfcontrole niet langer promoten, maar dat ze ook niet zeggen dat het zinloos is. Het is net als bij moedervlekken, die controleer je ook niet gestructureerd, maar als je een verandering ziet ga je wel naar de huisarts. Daarmee in overeenstemming zei de directeur van Pink Ribbon dat 90% van de vrouwen borstkanker zelf opmerkt: als er iets zit merk je het toch wel, bijvoorbeeld tijdens het douchen. Inderdaad kan ik dat uit eigen ervaring bevestigen. Mijn moeder voelde jaren geleden een knobbeltje terwijl ze zich aan het douchen was (kwaardaardig, maar genezen).

De Cochrane auteurs zeggen in hun review ook heel expliciet dat het absoluut noodzakelijk is om naar de dokter te gaan als vrouwen veranderingen aan hun borst opmerken.

“Some women will continue with breast self-examination or will wish to be taught the technique. We suggest that the lack of supporting evidence from the two major studies should be discussed with these women to enable them to make an informed decision.
It would be wrong, however, to conclude that women need not be aware of any breast changes. It is possible that increased breast awareness may have contributed to the decrease in mortality from breast cancer that has been noted in some countries. Women should, therefore, be encouraged to seek medical advice if they detect any change in their breasts that may be breast cancer.”

Hier is de Podcast waarin de Cochrane auteurs over hun studie vertellen.

Download:

zie Engels gedeelte hierboven








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