Why Publishing in the NEJM is not the Best Guarantee that Something is True: a Response to Katan

In a previous post [1] I reviewed a recent  Dutch study published in the New England Journal of Medicine (NEJM [2] about the effects of sugary drinks on the body mass index of school children.

The study got widely covered by the media. The NRC, for which the main author Martijn Katan works as a science columnist,  columnist, spent  two full (!) pages on the topic -with no single critical comment-[3].
As if this wasn’t enough, the latest column of Katan again dealt with his article (text freely available at mkatan.nl)[4].

I found Katan’s column “Col hors Catégorie” [4] quite arrogant, especially because he tried to belittle a (as he called it) “know-it-all” journalist who criticized his work  in a rivaling newspaper. This wasn’t fair, because the journalist had raised important points [5, 1] about the work.

The piece focussed on the long road of getting papers published in a top journal like the NEJM.
Katan considers the NEJM as the “Tour de France” among  medical journals: it is a top achievement to publish in this paper.

Katan also states that “publishing in the NEJM is the best guarantee something is true”.

I think the latter statement is wrong for a number of reasons.*

1. First, most published findings are false [6]. Thus journals can never “guarantee”  that published research is true.
   Factors that  make it less likely that research findings are true include a small effect size,  a greater number and lesser preselection of tested relationships, selective outcome reporting, the “hotness” of the field (all applying more or less to Katan’s study, he also changed the primary outcomes during the trial[7]), a small study, a great financial interest and a low pre-study probability (not applicable) .
2. It is true that NEJM has a very high impact factor. This is  a measure for how often a paper in that journal is cited by others. Of course researchers want to get their paper published in a high impact journal. But journals with high impact factors often go for trendy topics and positive results. In other words it is far more difficult to publish a good quality study with negative results, and certainly in an English high impact journal. This is called publication bias (and language bias) [8]. Positive studies will also be more frequently cited (citation bias) and will more likely be published more than once (multiple publication bias) (indeed, Katan et al already published about the trial [9], and have not presented all their data yet [1,7]). All forms of bias are a distortion of the “truth”.
   (This is the reason why the search for a (Cochrane) systematic review must be very sensitive [8] and not restricted to core clinical journals, but even include non-published studies: for these studies might be “true”, but have failed to get published).
3. Indeed, the group of Ioannidis  just published a large-scale statistical analysis[10] showing that medical studies revealing “very large effects” seldom stand up when other researchers try to replicate them. Often studies with large effects measure laboratory and/or surrogate markers (like BMI) instead of really clinically relevant outcomes (diabetes, cardiovascular complications, death)
4. More specifically, the NEJM does regularly publish studies about pseudoscience or bogus treatments. See for instance this blog post [11] of ScienceBased Medicine on Acupuncture Pseudoscience in the New England Journal of Medicine (which by the way is just a review). A publication in the NEJM doesn’t guarantee it isn’t rubbish.
5. Importantly, the NEJM has the highest proportion of trials (RCTs) with sole industry support (35% compared to 7% in the BMJ) [12] . On several occasions I have discussed these conflicts of interests and their impact on the outcome of studies ([13, 14; see also [15,16] In their study, Gøtzsche and his colleagues from the Nordic Cochrane Centre [12] also showed that industry-supported trials were more frequently cited than trials with other types of support, and that omitting them from the impact factor calculation decreased journal impact factors. The impact factor decrease was even 15% for NEJM (versus 1% for BMJ in 2007)! For the journals who provided data, income from the sales of reprints contributed to 3% and 41% of the total income for BMJ and The Lancet.
   A recent study, co-authored by Ben Goldacre (MD & science writer) [17] confirms that  funding by the pharmaceutical industry is associated with high numbers of reprint orders. Again only the BMJ and the Lancet provided all necessary data.
6. Finally and most relevant to the topic is a study [18], also discussed at Retractionwatch[19], showing that  articles in journals with higher impact factors are more likely to be retracted and surprise surprise, the NEJM clearly stands on top. Although other reasons like higher readership and scrutiny may also play a role [20], it conflicts with Katan’s idea that  “publishing in the NEJM is the best guarantee something is true”.

I wasn’t aware of the latter study and would like to thank drVes and Ivan Oranski for responding to my crowdsourcing at Twitter.

@laikas re: "NEJM publishing is the best guarantee something is true" - Incorrect, of course. Just look at the retractions, etc.

— Ves Dimov, M.D. (@DrVes) October 20, 2012

@laikas The NEJM has the highest Retraction Index, which has caveats but may be useful for your purposes: http://t.co/vhaM72XS

— Ivan Oransky (@ivanoransky) October 20, 2012

References

1. Sugary Drinks as the Culprit in Childhood Obesity? a RCT among Primary School Children (laikaspoetnik.wordpress.com)
2. 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, 367 (15), 1397-406 PMID: 22998340
3. NRC Wim Köhler Eén kilo lichter.NRC | Zaterdag 22-09-2012 (http://archief.nrc.nl/)
4. Martijn Katan. Col hors Catégorie [Dutch], (published in de NRC,  (20 oktober)(www.mkatan.nl)
5. Hans van Maanen. Suiker uit fris, De Volkskrant, 29 september 2012 (freely accessible at http://www.vanmaanen.org/)
6. Ioannidis, J. (2005). Why Most Published Research Findings Are False PLoS Medicine, 2 (8) DOI: 10.1371/journal.pmed.0020124
7. Changes to the protocol http://clinicaltrials.gov/archive/NCT00893529/2011_02_24/changes
8. Publication Bias. The Cochrane Collaboration open learning material (www.cochrane-net.org)
9. de Ruyter JC, Olthof MR, Kuijper LD, & Katan MB (2012). Effect of sugar-sweetened beverages on body weight in children: design and baseline characteristics of the Double-blind, Randomized INtervention study in Kids. Contemporary clinical trials, 33 (1), 247-57 PMID: 22056980
10. Pereira, T., Horwitz, R.I., & Ioannidis, J.P.A. (2012). Empirical Evaluation of Very Large Treatment Effects of Medical InterventionsEvaluation of Very Large Treatment Effects JAMA: The Journal of the American Medical Association, 308 (16) DOI: 10.1001/jama.2012.13444
11. Acupuncture Pseudoscience in the New England Journal of Medicine (sciencebasedmedicine.org)
12. Lundh, A., Barbateskovic, M., Hróbjartsson, A., & Gøtzsche, P. (2010). Conflicts of Interest at Medical Journals: The Influence of Industry-Supported Randomised Trials on Journal Impact Factors and Revenue – Cohort Study PLoS Medicine, 7 (10) DOI: 10.1371/journal.pmed.1000354
13. One Third of the Clinical Cancer Studies Report Conflict of Interest (laikaspoetnik.wordpress.com)
14. Merck’s Ghostwriters, Haunted Papers and Fake Elsevier Journals (laikaspoetnik.wordpress.com)
15. Lexchin, J. (2003). Pharmaceutical industry sponsorship and research outcome and quality: systematic review BMJ, 326 (7400), 1167-1170 DOI: 10.1136/bmj.326.7400.1167
16. Smith R (2005). Medical journals are an extension of the marketing arm of pharmaceutical companies. PLoS medicine, 2 (5) PMID: 15916457 (free full text at PLOS)
17. Handel, A., Patel, S., Pakpoor, J., Ebers, G., Goldacre, B., & Ramagopalan, S. (2012). High reprint orders in medical journals and pharmaceutical industry funding: case-control study BMJ, 344 (jun28 1) DOI: 10.1136/bmj.e4212
18. Fang, F., & Casadevall, A. (2011). Retracted Science and the Retraction Index Infection and Immunity, 79 (10), 3855-3859 DOI: 10.1128/IAI.05661-11
19. Is it time for a Retraction Index? (retractionwatch.wordpress.com)
20. Agrawal A, & Sharma A (2012). Likelihood of false-positive results in high-impact journals publishing groundbreaking research. Infection and immunity, 80 (3) PMID: 22338040

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* Addendum: my (unpublished) letter to the NRC

Tour de France.

Nadat het NRC eerder 2 pagina’ s de loftrompet over Katan’s nieuwe studie had afgestoken, vond Katan het nodig om dit in zijn eigen column dunnetjes over te doen. Verwijzen naar je eigen werk mag, ook in een column, maar dan moeten wij daar als lezer wel wijzer van worden. Wat is nu de boodschap van dit stuk “Col hors Catégorie“? Het beschrijft vooral de lange weg om een wetenschappelijke studie gepubliceerd te krijgen in een toptijdschrift, in dit geval de New England Journal of Medicine (NEJM), “de Tour de France onder de medische tijdschriften”. Het stuk eindigt met een tackle naar een journalist “die dacht dat hij het beter wist”. Maar ach, wat geeft dat als de hele wereld staat te jubelen? Erg onsportief, omdat die journalist (van Maanen, Volkskrant) wel degelijk op een aantal punten scoorde. Ook op Katan’s kernpunt dat een NEJM-publicatie “de beste garantie is dat iets waar is” valt veel af te dingen. De NEJM heeft inderdaad een hoge impactfactor, een maat voor hoe vaak artikelen geciteerd worden. De NEJM heeft echter ook de hoogste ‘artikelterugtrekkings’ index. Tevens heeft de NEJM het hoogste percentage door de industrie gesponsorde klinische trials, die de totale impactfactor opkrikken. Daarnaast gaan toptijdschriften vooral voor “positieve resultaten” en “trendy onderwerpen”, wat publicatiebias in de hand werkt. Als we de vergelijking met de Tour de France doortrekken: het volbrengen van deze prestigieuze wedstrijd garandeert nog niet dat deelnemers geen verboden middelen gebruikt hebben. Ondanks de strenge dopingcontroles.

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

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]

References

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

Related articles

• Studies more firmly tie sugary drinks to obesity (news.yahoo.com)
• Teens who cut out sugary drinks slowed weight gain (usatoday.com)
• Evidence against soda is piling up – Philadelphia Inquirer (philly.com)
• Can It! Soda Studies Cite Stronger Link to Obesity (nlm.nih.gov)

HOT TOPIC: Does Soy Relieve Hot Flashes?

The theme of the Upcoming Grand Rounds held at June 21th (1st day of the Summer) at Shrink Rap is “hot”. A bit far-fetched, but aah you know….shrinks“. Of course they hope  assume  that we will express Weiner-like exhibitionism at our blogs. Or go into spicy details of hot sexpectations or other Penis Friday NCBI-ROFL posts. But no, not me, scientist and librarian to my bone marrow. I will stick to boring, solid science and will do a thorough search to find the evidence. Here I will discuss whether soy really helps to relieve hot flashes (also called hot flushes).

…..As illustrated by this HOT picture, I should post as well…..

(CC from Katy Tresedder, Flickr):

Yes, many menopausal women plagued by hot flashes take their relief  in soy or other phytoestrogens (estrogen-like chemicals derived from plants). I know, because I happen to have many menopausal women in my circle of friends who prefer taking soy over estrogen. They rather not take normal hormone replacement therapy, because this can have adverse effects if taken for a longer time. Soy on the other hand is considered a “natural remedy”, and harmless. Probably physiological doses of soy (food) are harmless and therefore a better choice than the similarly “natural” black cohosh, which is suspected to give liver injury and other adverse effects.

But is soy effective?

I did a quick search in PubMed and found a Cochrane Systematic Review from 2007 that was recently edited with no change to the conclusions.

This review looked at several phytoestrogens that were offered in several ways, as: dietary soy (9x) (powder, cereals, drinks, muffins), soy extracts (9x), red clover extracts (7x, including Promensil (5x)), Genistein extract , Flaxseed, hop-extract  and a Chinese medicinal herb.

Thirty randomized controlled trials with a total of 2730 participants met the inclusion criteria: the participants were women in or just before their menopause complaining of vasomotor symptoms (thus having hot flashes) for at least 12 weeks. The intervention was a food or supplement with high levels of phytoestrogens (not any other herbal treatment) and this was compared with placebo, no treatment or hormone replacement therapy.

Only 5 trials using the red clover extract Promensil were homogenous enough to combine in a meta-analysis. The effect on one outcome (incidence of hot flashes) is shown below. As can be seen at a glance, Promensil had no significant effect, whether given in a low (40 mg/day) or a higher (80 mg/day) dose. This was also true for the other outcomes.

The other phytoestrogen interventions were very heterogeneous with respect to dose, composition and type. This was especially true for the dietary soy treatment. Although some of the trials showed a positive effect of phytoestrogens on hot flashes and night sweats, overall, phytoestrogens were no better than the comparisons.

Most trials were small,  of short duration and/or of poor quality. Fewer than half of the studies (n=12) indicated that allocation had been concealed from the trial investigators.

One striking finding was that there was a strong placebo effect in most trials with a reduction in frequency of hot flashes ranging from 1% to 59% .

I also found another systematic review in PubMed by Bolaños R et al , that limited itself only to soy. Other differences with the Cochrane Systematic Review (besides the much simpler search 😉 ) were: inclusion of more recently published clinical trials, no inclusion of unpublished studies and less strict exclusion on basis of low methodological quality. Furthermore, genestein was (rightly) considered as a soy product.

The group of studies that used soy dietary supplement showed the highest heterogeneity. Overall, the results “showed a significant tendency(?)  in favor of soy. Nevertheless the authors conclude (similar to the Cochrane authors), that  it is still difficult to establish conclusive results given the high heterogeneity found in the studies. (but apparently the data could still be pooled?)

References

• Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, & Brown J. (2007). Phytoestrogens for vasomotor menopausal symptoms Cochrane Database of Systematic Reviews (4) : 10.1002/14651858.CD001395.pub3.
• Bolaños R, Del Castillo A, & Francia J (2010). Soy isoflavones versus placebo in the treatment of climacteric vasomotor symptoms: systematic review and meta-analysis. Menopause (New York, N.Y.), 17 (3), 660-6 PMID: 20464785

Breast Cancer is not a Pink Ribbon.

I have always had mixed feelings in case of large happenings like marches and ribbon activities and cancer months. September is the ovarian cancer month (and also a US Prostate Cancer Month and a childhood cancer month) and  October the breast cancer month…. We have only 12 months in a year!

Please, don’t misunderstand me! Awareness is very important, also in the case of breast cancer: Awareness so to recognize breast cancer in an early stage, awareness of preventive measures of cancer,  awareness what women with breast cancer go through, awareness that breast cancer often can be cured, awareness that research is needed, and thus money.

But I also feel that the attention is overdone and often hypocritical, with fancy pink ribbons and “pink”: everywhere. This feeling is strengthened by some recent articles. For instance this article in Health.Chance.org, called Pink Ribbon Hypocrisy: Boozing It Up for Breast Cancer discussing that fast food and alcohol companies Use Breast Cancer as a Marketing Ploy (whereas these items some reputation if it comes to -certain types of- cancer). You can sign a petition here against it.

There is even a book Pink Ribbon Blues – How Breast Cancer Culture Undermines Women’s Health, written by Gayle A. Sulik, that is “thought-provoking and probing argument against the industry of awareness-raising”

From the description:

Pink ribbon paraphernalia saturate shopping malls, billboards, magazines, television, and other venues, all in the name of breast cancer awareness. (…) Gayle Sulik shows that though this “pink ribbon culture” has brought breast cancer advocacy much attention, it has not had the desired effect of improving women’s health. It may, in fact, have done the opposite. Based on eight years of research, analysis of advertisements and breast cancer awareness campaigns, and hundreds of interviews with those affected by the disease, Pink Ribbon Blues highlights the hidden costs of the pink ribbon as an industry, one in which breast cancer has become merely a brand name with a pink logo.

The following quote from a woman who had lost her mother to breast cancer illustrates the feeling of many (see comments):

As the years went by, life provided me with more reasons to hate pink. Frustration over society-defined gender roles piled on as did annoyance at the image of ultimate feminine woman. And then came the big one.

Breast cancer.

My mom passed away after a six-year long battle with breast cancer at the age of 45.

When pink later became symbolic of breast cancer awareness, I wanted to punch some pink piggies. I know that some people choose to wear pink to honor or remember or show support for a loved one. That is not what I get my panties in a bunch about–it’s the way corporate America has grabbed that pink flag and waved it to and fro for their own profit that makes me furious.

I remember once standing in the grocery store and staring at a bag of pink ribbon-adorned M&Ms, my blood boiling harder with every passing second.

She ends her post with:

Everyone has a story. Some have seen the scars of a mastectomy. Some have witnessed the toll that chemotherapy takes on a body. Some have lived the pain. We all know it’s bad.

I, for one, don’t need pink to remind me.

That same is true for me. I’ve seen my mother battling breast cancer -she is a survivor- and I have seen the scars of mastectomy and these are nowhere near pink ribbon.

“Breast Cancer is not a Pink Ribbon” tweeted Gilles Frydman yesterday and he meant a great pictures exhibition that lasted 3 days, showing portraits of young topless breast cancer survivors shot by fashion photographer David Jay.

At first I found it mainly confronting: this is the reality of breast cancer! As described elsewhere (Jezebel):

Seeing scarred and reconstructed mammary glands is not just shocking because of the way breasts are fetishized in our society, but because it speaks to how much we hide, gloss over and tidy up disease. Breasts are one of the defining physical attributes for identifying a woman. Breast cancer eats away at flesh meant to nourish. Surgery is a brutal procedure from which to recover and heal. But cute, clean, pink ribbons have come to symbolize all that.

But at a second and third look, I mainly saw the beauty of the photo’s, the fierceness of the women and their beautiful eyes.

Exactly as put into words at the website of the SCAR project:

Although Jay began shooting The SCAR Project primarily as an awareness raising campaign he was not prepared for something much more immediate . . . and beautiful: “For these young women, having their portrait taken seems to represent their personal victory over this terrifying disease.

SCAR by the way stands for ‘Surviving Cancer. Absolute Reality.”

David Jay was inspired to act when a dear friend was diagnosed with breast cancer at the age of 32.

The SCAR-project is “dedicated to the more than 10,000 women under the age of 40 who will be diagnosed this year alone The SCAR Project is an exercise in awareness, hope, reflection and healing. The mission is three-fold: Raise public consciousness of early-onset breast cancer, raise funds for breast cancer research/outreach programs and help young survivors see their scars, faces, figures and experiences through a new, honest and ultimately empowering lens.”

The exhibition was last week in New York, but you can still see the photographs at the website of the SCAR-project.

Furthermore, you can participate in the project and/or buy the (signed) SCAR project book ($55).

Related Articles

• Pink Ribbon Fatigue: 8 Ways to Support Breast Cancer Awareness Even If You Hate Pink (blisstree.com)
• Jackass Steve-O Believes Breast Cancer Awareness Is More Than Just Pink Ribbons (ecorazzi.com)
• SCAR Project Exposes The Realities Of Breast Cancer [Art] (jezebel.com)
• “Like A Pink Punch To The Gut” and related posts (theburghbaby.com)
• The pink-ribbon backlash (theglobeandmail.com)
• Pink Ribbon Fatigue (well.blogs.nytimes.com)

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

“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.

Vodpod videos no longer available.
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.

Vodpod videos no longer available.

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

• Wikipedia Commons: Healthcare spending as %25 GDP
• Unemployed single mother, from the NY-times, Ref  [1]
• Animated graph: International health data changing the parameters produces different graphs (2 shown). The data for the graph can be found in the Organisation for Economic Co-operation and Development’s Health Data 2009 see ref [4]
  

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.

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• Health Care Reform (timesunion.com)
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• Jarrett on Health Care: Businesses Will Come Out ‘Way Ahead’ (blogs.abcnews.com)
• Health care reform deep thought (trueslant.com)

Sugar-Sweetened Beverages, Diet Coke & Health. Part I.

At Medical and Technology of Joseph Kim, the upcoming Grand Rounds host, I saw the blog post “Need your help on Facebook to get Diet Coke to Donate $50,000 to the Foundation for NIH”.

National Heart Lung and Blood Institute has started a national campaign in the US, The Heart Truth^®. They issued a challenge in support of heart health, raising awareness on the fact that  heart disease is the #1 killer of women, to identify risk factors and take action to lower them. Diet Coke is one of their corporate-partners, helping to spread the word through visibility on 6.7 billion packages of Diet Coke featuring The Heart Truth and Red Dress symbol. It has also started a Facebook cause: Diet Coke will donate $0.50 for every person that joins the cause and $1.00 for every person that donates $1, for a total donation of up to $50,000!

O.k. Donation Fine, NIH fine, but Coca Cola as a main sponsor to raise awareness against heart disease?? Its almost feels like a tobacco company raising awareness against lung cancer. It is as odd as McDonalds, Lego & Mars preaching online advertising awareness to kids...

You could object that any money to raise awareness is  a welcome bonus and that diet coke, unlike normal coke, doesn’t contain any calories. But then you could ask whether diet coke is really healthy… Plus Coca Cola does sell a lot of beverages with loads of sugar, with a possible adverse effect on health, including cardiovascular disease (see below). It looks a lot like hypocrisy to me, meant only to improve the BRAND.

Well, I was to write about sweetened beverages anyway, since I came across several interesting news items the last weeks.

Sugar-Sweetened Beverages Have Major Effects on Diabetes and Cardiovascular Health

During the joint EPI/NPAM Conference (Cardiovascular Disease Epidemiology and Prevention &- Nutrition, Physical Activity and Metabolism), Mar 2-5, 2010 (link), Litsa Lambrakos presented a poster “Sugar-Sweetened Beverage Consumption and the Attributable Burden to Diabetes and Coronary Heart Disease” that was covered in a press release and in the media (Elsevier Global Medical News; All Headline News)

Based on data from several large observational studies demonstrating a link between higher rates of sugar-sweetened beverages (SSB) consumption and subsequent risk of incident diabetes, Lambrakos and colleagues assumed that daily consumption of SSBs is associated with an increased risk of incident diabetes (RR 1.32 for those with daily consumption compared with adults consuming less than one sugar-sweetened beverage per month).  Next they estimated that the increased consumption of sugar-sweetened beverages (including sugar-sweetened soda, sport and fruit drinks) between 1990 and 2000 contributed to 130,000 new cases of diabetes, 14,000 new cases of coronary heart disease (CHD), and 50,000 additional life-years burdened by coronary heart disease over the past decade. They derived these data from the 1990-2000 National Health and Nutrition Examination Survey (NHANES) on consumption of sugar-sweetened beverages, combined  with the CHD Policy Model, a computer simulation of heart disease in U. S. adults aged 35-84 years.

Through the model, the researchers also estimated that the additional disease caused by the drinks has increased coronary heart disease healthcare costs by 300-550 million U.S. dollars between 2000-2010. This is probably an underestimation, because it does not account for the increased costs associated with the treatment and care of patients with diabetes alone.

How does this ($300.000.000-$550.000.000) compare to the $50,000 (max) that Coca Cola is willing to contribute to The Heart Truth?

Admitted, the comparison is not entirely fair. There are far more soft drinks than the sodas from Coca Cola. More importantly, the reliability of the  figures is highly dependent on the accuracy of the assumptions. Furthermore it is hard to review a study that is not yet published.

Other studies on possible harm of SSB consumption. 1. Effects on BMI, overweight & obesity.

To get an idea about the evidence on the ‘harm’ of SSB I did a quick search in PubMed (see PubMed tips).

First I searched for secondary (aggregated) sources.

((Dietary Sucrose AND beverages) OR soft drink* OR sugar-sweetened beverag* OR soda*[tiab]) AND “systematic”[Filter]

This yielded 27 hits.

Five Publications centered on the effect of beverages on weight, obesity or BMI.

The effect on overweight seems the most obvious side-effect of SSB’s. First the increase in obesity over time has been paralleled by an increase in soft drink consumption. Second the daily sweetener consumption in the United States increased by 83 kcal per person, of which 54 kcal/d  from soda. If these calories are added to the normal diet without reducing intake from other sources, 1 soda/d could lead to a weight gain of 6.75 kg in 1 year. [refs in 2]

Still the evidence is not that clear.

Malik [2], and an almost overlapping systematic review [3] conclude that large cross-sectional studies, well-powered prospective cohort studies with long follow-up, and short-term experimental studies (including 2 RCT’s), show a positive association between greater intakes of SSBs and weight gain and obesity in both children and adults and yield sufficient evidence for public health strategies to discourage consumption of sugary drinks as part of a healthy lifestyle.

Two later reviews [4,5] point out that Malik et al. had erroneously concluded that the evidence was ‘strong’, because “several studies were reported as positive when only a selected sub-group had a positive result, or classified as ‘positive non-significant’ where coefficients are near zero and P values in excess of 0·2. Furthermore, the results of two studies were confounded by the inclusion of diet soft drinks.”[4]

On the contrary, Forshee et al [4] conclude that the  association between SSB consumption and BMI was near zero. Interestingly, the funnel plot analysis was consistent with publication bias against studies that do not report statistically significant findings!

Gibson [5] concludes that that the effect of SSB on body weight is small except in susceptible individuals or at high levels of intake. She also points out that the totality of evidence is dominated by American studies (including the positive NHANES study), “that may be less applicable to the European context where consumption is substantially lower and composition or formulation may differ (high-fructose corn syrup v. sucrose, proportion of diet v. non-diet, etc).”
Indeed in a systematic review primarily including European studies [6], overweight was not associated with the intake of soft drinks, but with lower physical activity and more tv watching time.

Thus the effect of SSB (alone) on BMI and overweight is inconclusive, based on the current body of evidence.

It is not excluded though that high intake of SSB alone or regular consumption of SSB in combination with other unhealthy lifestyle factors (unsaturated fat, lower physical activity) do contribute to obesity.

Since lack of sleep is also unhealthy (and possibly obesogen), I will leave it here.

Next time I will discuss any cardiovascular or other harmful effects of sugar sweetened beverages ànd diet sodas.

Meanwhile enjoy the sugar and coca cola video below.

Whatever the evidence, daily consumption of SSB, with many calories and no nutritional value, doesn’t seem overtly healthy to me. I won’t allow my kids to drink soda as a habit.

References

1. Litsa K Lambrakos, Pamela Coxson, Lee Goldman, Kirsten Bibbins-Domingo (2010). Sugar-Sweetened Beverage Consumption and the Attributable Burden to Diabetes and Coronary Heart Disease, poster  365, Joint Cardiovascular Disease Epidemiology and Prevention &- Nutrition, Physical Activity and Metabolism – Conference Mar 2-5, 2010.
2. Malik VS, Schulze MB, & Hu FB (2006). Intake of sugar-sweetened beverages and weight gain: a systematic review. The American journal of clinical nutrition, 84 (2), 274-88 PMID: 16895873
3. Wolff E, & Dansinger ML (2008). Soft drinks and weight gain: how strong is the link? Medscape journal of medicine, 10 (8) PMID: 18924641
4. Forshee RA, Anderson PA, & Storey ML (2008). Sugar-sweetened beverages and body mass index in children and adolescents: a meta-analysis. The American journal of clinical nutrition, 87 (6), 1662-71 PMID: 18541554
5. Gibson S (2008). Sugar-sweetened soft drinks and obesity: a systematic review of the evidence from observational studies and interventions. Nutrition research reviews, 21 (2), 134-47 PMID: 19087367
6. Janssen I, Katzmarzyk PT, Boyce WF, Vereecken C, Mulvihill C, Roberts C, Currie C, Pickett W, & Health Behaviour in School-Aged Children Obesity Working Group (2005). Comparison of overweight and obesity prevalence in school-aged youth from 34 countries and their relationships with physical activity and dietary patterns. Obesity reviews : an official journal of the International Association for the Study of Obesity, 6 (2), 123-32 PMID: 15836463

Photo Credits

1. Diet Coke: http://en.wikipedia.org/wiki/File:Diet_Coke_can_US_1982.jpg
2. Sugar in Coca Cola: http://www.sugarstacks.com/

They used data from the 1990-2000 National Health and Nutrition Examination Survey (NHANES) on consumption of sugar-sweetened beverages. She combined that with the Coronary Heart Disease Policy Model, a computer simulation of heart disease in U. S. adults aged 35-84 years.

Food for Thought

Food is important. Without food we starve, but too high caloric intake or eating too much of certain foods can result in diabetes type 2, cardiovascular diseases and other health problems. On the other hand foods can also protect us against  diseases. For instance cauliflower and broccoli can reduce the risk to get certain cancers.

Nowadays, obesity is a major health problem, not only among adults, but even among children and teenagers.

According to the CDC:

The prevalence of obesity among children aged 6 to 11 more than doubled in the past 20 years, going from 6.5% in 1980 to 17.0% in 2006. The rate among adolescents aged 12 to 19 more than tripled, increasing from 5% to 17.6%. Obesity is the result of caloric imbalance (too few calories expended for the amount of calories consumed) and is mediated by genetics and health.

Childhood obesity also rising rapidly in the Netherlands, as well as in other countries all over the world.

Fat often gets the blame for obesity and health problems.

As a result some parents are avoiding fats in their food and keep fats from the diets of kids as well. Elise Buiting, chair of the youth service medical association (Artsen Jeugdgezondheidszorg Nederland , AJN) urges that the low-fat trend is disadvantageous for young children. This causes them to be to thin and too short for their age. A child’s diet should contain 30–40% of energy from fat. Furthermore, children need fat for their developing brain. And too low fat intake may lead to a too low intake of certain fat-soluble vitamins. (see recent interview in “de Pers“[NL]

In one other interview [EN] she said:

‘Children under the age of six need fat. We recommend full-fat yogurt for example,’ (..) ‘Children who are given the same light products as their parents eat do not get enough.’

Some parents not only omit butter and full-fat diary but may use low-fat products with relatively large quantities of artificial sweetener, but children should keep away from the  aspartame that they contain.

Buiting bases her ideas on the reports from child health centers and from the The Dutch National Food Consumption Survey (DNFSC). In their 2005/2006 report the authors of the DNFSC conclude:

A food consumption survey of young children (2 to 6 years of age) in the Netherlands has shown the diet to be adequate in terms of the proportions of total fat, carbohydrates and protein. However, the fatty acid composition of the diet is unfavourable, because fish consumption (rich in fish fatty acids) is low, and saturated fatty acid intake especially in 4 to 6 year-old children is high. Only a small proportion of children meet the recommended vegetable intake. For fruit the situation is slightly more favourable (one in four). Furthermore, one in seven children was found to be overweight or obese.

So the latter data do point in another direction for the majority of young children in the Netherlands: high energy-intake, an unbalanced diet and too much saturated fat. A healthy balanced diet would also mean sufficient fat intake, in particular of the unsaturated kind.

You might also like:

Some sugars worse than others.The bittersweet fructoseglucose debate (laikaspoetnik.wordpress.com)

Photo Credit

Thin & ʞɔıɥʇ button: http://www.flickr.com/photos/ntr23/ / CC BY-NC-SA 2.0

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Hot News: Curry, Curcumin, Cancer & Cure

*Hot* News via Twitter and various news media a few days ago. Big headlines tell the following in respectively The Sun, Herald, Ireland, BBC News / NHS Health and Reuters:

Curry is a ‘cure for cancer‘

Spices in curry may help cure cancer

Curry spice ‘kills cancer cells‘

Scientists say curry compound kills cancer cells

The message of these headlines is quite different and so are the articles themselves (covered more in depth by @jdc325 at the BadScience Blog “Stuff and Nonsense” (see here)). They vary from “curry being a cure for cancer” to “a possible effect of one of its compounds on cancer cells”.

So what was (not) done?

1. Cancer was not cured.
2. It was not a human trial.
3. The study didn’t test effects on living laboratory animals, like mice, either.
4. The study was done in the test tube, using individual cancer cell lines.
5. The cells tested were (only) esophageal cancer cell lines.
6. Testing the drugs efficacy was not the main aim of the study.
7. Curry (a complex spicy mixture) wasn’t used.
8. Curcumin was tested, which makes up 3% of “turmeric”, that is one of the spices in curry.
9. That curcumin has some anti-carcinogenic effects is not new (see my tweet linking to 1120 hits in PubMed with a  simple PubMed search for curcumin and cancer: http://bit.ly/3Qydc6)

So why the fuss? This doesn’t seem to be a terribly shocking study. Why the media picked this one up is unclear. It must have been, because they were sleeping (missed all the previous studies on curcumin) and/or because they are fond of these kind of studies: except from the experimental details- these studies translate so well to the general public: food – cure – cancer.

And the headlines do it much better than the actual title of the article:

Curcumin induces apoptosis-independent death in oesophageal cancer cells

I experienced the same when my study was picked up at a cancer conference by BBC-health, whereas other far more pioneering studies were not: these were harder to grasp and to explain ‘to the public’ and without any possible direct health benefit.

What was already known about curcumin and cancer? What was done in the present study? What is new? And is curcumin really a promising agent?

Already known.

Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. It gives the curry it bright yellow color. Curcumin has a plethora of beneficial effects in vitro (in the test tube) and in animal studies, including anti-microbial,  anti-arthritic and  anti-inflammatory effects, but most interesting is its anti-carcinogenic effect. It has potential for both prevention and therapy of cancer, but the evidence for preventive effects is most convincing. The mechanisms playing a role in the anticarcinogenic effect are also multifold and complex. Possible mechanisms include: Inhibition/protection from DNA damage/alterations, Inhibition of angiogenesis, Inhibition of invasion/metastasis, Induction of apoptosis, Antioxidant activity, Induction of GST, Inhibition of cytochromes P450, I NF-jB, AP-1, MMPs, COX-2, TNF-a, IL-6, iNOS, IL-1b, the oncogens ras/fos/jun/myc, MAPK, ornithine decarboxylase, Activation of Nrf2, Induction of HO-1, Activation of PPAR-c  and Immunostimulant/immunorestorer effect……….[2]

New Findings

This is to put in perspective that the researchers found yet another possible mechanism (although others have found evidence before, see introduction [1]). Using a small panel of esophagus cancer cells, they first showed that the cells were selectively killed by curcumin. Next they showed that the major mechanism wasn’t apoptosis, cell death by suicide, but cell death by a mechanism called “Mitotic catastrophe”, a type of cell death that occurs during mitosis (cell division) (see free review in Oncogene [3]). As with apoptosis many steps have to go wrong before the cell will undergo mitotic catastrophe. The researchers show that curcumin-responsive cells were found to accumulate poly-ubiquitinated proteins and cyclin B, consistent with a disturbance of the ubiquitin–proteasome system: ubiquitin labels proteins for degradation by proteasomes, thereby controlling the stability, function, and intracellular localization of a wide variety of proteins.

In other words, this study is mainly about the mechanisms behind the anti-cancer effects of curcumin.

Cure?

Of course this paper itself has no direct relevance to the management of human esophagus cancer. The sentence that may have triggered the media is:

“Curcumin can induce cell death by a mechanism that is not reliant on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of esophageal cancer.”

Which is of course to far-fetched. The authors refer to the fact that esophageal cancers are often resistant to cell death induction with chemotherapeutic drugs, but this only indirectly points at a possible role for curcumin.

It has to be stressed that no human study has convincingly shown an anti-tumor effects of curcumin. Studies that have been done are observational, i.e. show that people taking higher concentrations of curcumin in their diet have a lower incidence of several common cancer types. However, such studies are prone to bias: several other factors (alone or in together) can be responsible for a anti-cancer effect (see previous post [5] explaining this for other nutrients).

The Current grade of evidence for a preventive or therapeutic effect is C, which means “unclear scientific evidence” (see MedlinePlus).

Although there are several trials under way there is reason to be skeptical about the potential of curcumin as cancertherapeutic agent.

• The limited bioavailability and extensive metabolism of curcumin suggest that many of its anticancer effects observed in vitro may not be attainable in vivo. On the other the gastro-intestinal system is he most likely place for an effect of curcimin taken by the oral route. [2]
• Although relatively high concentrations of curcumin have not shown significant toxicity in short-term studies, these concentrations may lead to toxic and carcinogenic effects in the long term.[2]
• The therapeutic effects are dose-dependent. As often seen with these bioactive compounds, toxic effects can occur at supra-optimal amounts. Indeed curcumin has shown to be toxic and carcinogenic under specific conditions. At low and high doses curcumin behaves as an anti-oxidant and a pro-oxidant (toxic) respectively. [2, 6 ]
• Often more ingredients add to the therapeutic effect, or more foods/habits [5].
• The FDA has a shortlist of “187 Fake Cancer “Cures” Consumers Should Avoid”, compounds containing curcumin are on that list [7].

Conclusion

So, concluding, a study that unraveled one of the mechanisms whereby curcumin can kill cancer cells, led to an exaggerated and sometimes completely wrong coverage in the media. Why this was done is unclear, but the ultimate result of such misplaced drumroll will only lead to disbelief or carelessness.

Shame on you, media!!

Photo credits

http://www.flickr.com/photos/trentstrohm/347513745/

References

1. O’Sullivan-Coyne, G., O’Sullivan, G., O’Donovan, T., Piwocka, K., & McKenna, S. (2009). Curcumin induces apoptosis-independent death in oesophageal cancer cells British Journal of Cancer, 101 (9), 1585-1595 DOI: 10.1038/sj.bjc.6605308
2. López-Lázaro, M. (2008). Anticancer and carcinogenic properties of curcumin: Considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent Molecular Nutrition & Food Research DOI: 10.1002/mnfr.200700238
3. Castedo, M., Perfettini, J., Roumier, T., Andreau, K., Medema, R., & Kroemer, G. (2004). Cell death by mitotic catastrophe: a molecular definition Oncogene, 23 (16), 2825-2837 DOI: 10.1038/sj.onc.1207528
4. Stuff and Nonsense – Curry can cure cancer, say scientists (2009/10/28)
5. The best study design for dummies (2008/08/25)
6. Huge disappointment: Selenium and Vitamin E fail to Prevent Prostate Cancer.(post on this blog about the SELECT trial – 2008/11/16)
7. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/ucm171057.htm

You may also want to read:

• MnSOD, Carotenoids & Prostate Cancer – “You are what you eat” depends on who you are. (2009/02/22/
• Yet another negative trial with vitamins in prostate cancer vitamins c and e (2008/12/15)

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• Curry compound killed cancer cells in lab (cbc.ca)

Some Sugars Worse than Others? The Bittersweet Fructose/Glucose Debate.

Excessive consumption of sugar has been associated with increased incidences of type 2 diabetes, formerly called adult-onset diabetes, obesity and tooth decay.

There are many sugars around. Natural sugars and refined sugars. The refined table sugar and sugar cubes would be called “sucrose” by a chemist. Sucrose consists of two simple sugars (monosaccharides): 1 fructose and 1 glucose molecule (5).

Glucose is a sugar that occurs in the blood. Because of its name, fructose (Latin= fructus, fruit) is often regarded as more “natural” and therefore as a healthier alternative to glucose. However, unlike glucose, that can be metabolized anywhere in the body, fructose has to be metabolized by the liver. Here, fructose is easily converted to fat.

There is an intensive debate whether glucose or fructose is the real culprit for overweight and related health problems. This discussion is  relevant, because of the shift towards use of (cheaper) high fructose corn syrup from sucrose (especially in the US).

Last week a journal article was published in the Journal of Clinical Investigation, written by Stanhope et al (1) that was widely covered in the media. Headlines were for instance “Fructose slechter dan glucose” (NRC, Dutch, 8), “Fructose is the bad sugar, not glucose” (Indo-Asian News Service, i.e. 9) “Fructose-Sweetened Beverages Linked to Heart Risks” (NY-times, 10).

Is this study a breakthrough? What has been done?

This study was a double-blinded parallel arm study that assessed the relative effects of fructose- versus glucose – sweetened beverages in 32 matched, obese individuals, 40 to 72 years old (see 1).

The study consisted of 3 phases:

1. The first 2 weeks the volunteers lived in a clinical research center, consuming an energy- balanced high complex carbohydrate diet. This phase established baseline measurements for the study.
   
2. An 8-week outpatient intervention period during which subjects consumed either fructose- or glucose-sweetened beverages providing 25% of daily energy requirements along with their usual ad libitum diet. The aim was to imitate the ‘normal situation’, where sugar-sweetened beverages are typically consumed as part a normal energy-rich diet.
3. A 2-week inpatient intervention period during which subjects consumed fructose- or glucose-sweetened beverages providing 25% of daily energy requirements with an energy-balanced diet.

Results

Both study groups put on the same amount of weight, but people drinking fructose showed an increase in intra-abdominal fat, an increased hepatic de-novo (new) synthesis of lipids, higher triglyceride, LDL and oxidized LDL (“bad fats”), and higher fasting plasma glucose and insulin levels, but lowered insulin sensitivity. All these parameters are associated with a higher risk for diabetes and cardiovascular disease.

Positive Aspects of the study

• Intervention directly comparing fructose and glucose
• Human study
• Randomized Controlled Trial
• Many variables measured, related to diabetes and cardiovascular disease.

Critique:

• The first thing that came to my mind was: is it ethical to expose obese man and woman (or any healthy volunteer) to 10 weeks of a very unhealthy diet: extra glucose or fructose beverages making up 25% of the calorie intake?
• Because the subjects were obese, the results may not directly apply to lean persons.
• Minor point: It is a rather difficult to read paper, with a plethora of data. I wonder why SEM are given instead of SD and why the statistical significance is only determined versus baseline.
• Only surrogate markers were tested.
• Most important: the doses of sugars used are excessive, not reflecting a real-life diet.
• Nor can results with pure fructose be directly translated to health effects of high-fructose corn syrup, which is not pure fructose, but still contains 45% glucose.
• In addition the abstract and introduction suggests that it is the first human intervention study, which it isn’t.

Quite coincidentally the Journal of Nutrition published a supplement about “the State of the Science on Dietary Sweeteners Containing Fructose” [2-4]. In his paper Geoffrey Livesey [2] stresses the pitfalls of studies on Fructose, not only of animal and epidemiological studies, but also of intervention studies using excessive high fructose (excessive is > 400 kcal/day = >20% of energy intake), that may bear little relevance to the normal situation.

Many hypotheses of disease risk and prevention depend on inferences about the metabolic effects of fructose; however, there is inadequate attention to dose dependency. Fructose is proving to have bidirectional effects. At moderate or high doses, an effect on any one marker may be absent or even the opposite of that observed at very high or excessive doses; examples include fasting plasma triglyceride, insulin sensitivity (..) Among markers, changes can be beneficial for some (..) but adverse for others (e.g., plasma triglycerides at very high or excessive fructose intake). Evidence on body weight indicates no effect of moderate to high fructose intakes, but information is scarce for high or excessive intakes. The overall balance of such beneficial and adverse effects of fructose is difficult to assess but has important implications for the strength and direction of hypotheses about public health, the relevance of some animal studies, and the interpretation of both interventional and epidemiological studies.

References:

1. Stanhope, K., Schwarz, J., Keim, N., Griffen, S., Bremer, A., Graham, J., Hatcher, B., Cox, C., Dyachenko, A., Zhang, W., McGahan, J., Seibert, A., Krauss, R., Chiu, S., Schaefer, E., Ai, M., Otokozawa, S., Nakajima, K., Nakano, T., Beysen, C., Hellerstein, M., Berglund, L., & Havel, P. (2009). Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans Journal of Clinical Investigation DOI: 10.1172/JCI37385
2. Livesey, G. (2009). Fructose Ingestion: Dose-Dependent Responses in Health Research Journal of Nutrition DOI: 10.3945/jn.108.097949
3. White, J. (2009). Misconceptions about High-Fructose Corn Syrup: Is It Uniquely Responsible for Obesity, Reactive Dicarbonyl Compounds, and Advanced Glycation Endproducts? Journal of Nutrition DOI: 10.3945/jn.108.097998
4. Jones, J. (2009). Dietary Sweeteners Containing Fructose: Overview of a Workshop on the State of the Science Journal of Nutrition DOI: 10.3945/jn.108.097972
5. Wikipedia: http://en.wikipedia.org/wiki/Sugar
   
6. Essentially Healthy Food: Sugar, a bittersweet story part 2
7. http://www.askmen.com/sports/foodcourt_250/257_health-benefits-of-sugar.html
8. NRC, April 21, 2009. http://www.nrc.nl/wetenschap/article2219138.ece/Fructose_slechter_dan_glucose
9. The Idian http://www.thaindian.com/newsportal/sci-tech/fructose-is-the-bad-sugar-not-glucose_100184408.html
10. NY Times,  April 2, 2009: Fructose-Sweetened Beverages Linked to Heart Risks

Photo Credits

• Sugarcube: http://www.flickr.com/photos/uwehermann/132244825/ (CC)
• Glucose/Frucose structure: http://www.elmhurst.edu/~chm/vchembook/543fructose.html
• Softdrinks: http://www.flickr.com/photos/tuis_imaging/3198244845/ (CC)
  

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

When 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.

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:

• The best study design for dummies (2008/08/25/)
• Huge disappointment: Selenium and Vitamin E fail to Prevent Prostate Cancer.(post on this blog about the SELECT trial – 2008/11/16)
• Yet another negative trial with vitamins in prostate cancer vitamins c and e (2008/12/15)

Photo Credits

• http://commons.wikimedia.org/wiki/File:Tomaten_im_Supermarktregal.jpg
• http://commons.wikimedia.org/wiki/File:Lycopene_in_DCM.jpg

Yet Another Negative Trial with Vitamins in Prostate Cancer: Vitamins C and E.

Within a week after the large SELECT (Selenium and Vitamin E Cancer Prevention) Trial was halted due to disappointing results (see previous posts: [1] and [2]), the negative results of yet another large vitamin trial were announced [7].
Again, no benefits were found from either vitamin C or E when it came to preventing prostate ànd other cancers.
Both trials are now prepublished in JAMA. The full text articles and the accompanying editorial are freely available [3, 4, 5].

In The Physicians’ Health Study II Randomized Controlled Trial (PHS II), researchers tested the impact of regular vitamin E and C supplements on cancer rates among 14,641 male physicians over 50: 7641 men from the PHS I study and 7000 new physicians.

The man were randomly assigned to receive vitamin E, vitamin C, or a placebo. Besides vitamin C or E, beta carotene and/or multivitamins were also tested, but beta carotene was terminated on schedule in 2003 and the multivitamin component is continuing at the recommendation of the data and safety monitoring committee.

Similar to the SELECT trial this RCT had a factorial (2×2) design with respect to the vitamins E and C [1]: randomization yielded 4 nearly equal-sized groups receiving:

• 400-IU synthetic {alpha}-tocopherol (vitamin E), every other day and placebo (similar to the SELECT trial)
• 500-mg synthetic ascorbic acid (vitamin C), daily and placebo
• both active agents
• both placebos.

Over 8 years, taking vitamin E had no impact at all on rates of either prostate cancer (the primary outcome for vitamin E), or cancer in general. Vitamin C had no significant effect on total cancer (primary outcome for vitamin C) and prostate cancer. Neither was there an effect of vitamin E and/or C on other site-specific cancers.

How can the negative results be explained in the light of the positive results of earlier trials?

• The conditions may differ from the positive trials:
  • The earlier positive trials had less methodological rigor. These were either observational studies or prostate cancer was not their primary outcome (and may therefore be due to chance). (See previous post The best study design for dummies).
  • Clinical data suggest that the positive effect of vitamin E observed in earlier trials was limited to smokers and/or people with low basal levels of vitamin E, whereas animal models suggest that vitamin E is efficacious against high fat-promoted prostate cancer growth (20), but lacks chemopreventive effects (i.e. see [1,4] and references in [5], a preclinical study we published in 2006).
    Indeed, there were very low levels of smoking in the PHS II study and the effect of the vitamins was mainly assessed on induction not on progression of prostate cancer.
  • 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! [1,4]
• Other forms of vitamin E and selenium have been proposed to be more effective.
• As Gann noted in the JAMA-editorial, the men in both recent studies were highly motivated and had good access to care. In SELECT, the majority of men were tested for PSA each year. Probably because of this intense surveillance, the mean PSA at diagnosis was low and prostate cancers were detected in an early, curable stage. Strikingly, there was only 1 death from prostate cancer in SELECT, whereas appr. 75-100 deaths were expected. There also were indications of a deficit in advanced prostate cancer in PHS II, although a much smaller one.
  In other words (Gann):
  “how can an agent be shown to prevent serious, clinically significant prostate cancers when PSA testing may be rapidly removing those cancers from the population at risk before they progress?”
• Similarly, in the SELECT trial there was no constraint on the use of other multivitamins and both studies put no restriction on the diet. Indeed the group of physicians who participated in the PHS II trial were healthier overall and ate a more nutritious diet. Therefore Dr Shao wondered
  “Do we really have a placebo group – people with zero exposure? None of these physicians had zero vitamin C and E” [7]. In the Netherlands we were not even able to perform a small phase II trial with certain nutrients for the simple reason that most people already took them.

What can we learn from these negative trials (the SELECT trial and this PHS II-trial)?

• Previous positive results were probably due to chance. In the future a better preselection of compounds and doses in Phase 2 trials should determine which few interventions make it through the pipeline (Gann, Schroder).
• Many other trials disprove the health benefits of high dose vitamins and some single vitamins may even increase risks for specific cancers, heart disease or mortality [9]. In addition vitamin C has recently been shown to interfere with cancer treatment [10].
• The trials make it highly unlikely that vitamins prevent the development of prostate cancer (or other cancers) when given as a single nutrient intervention. Instead, as Dr Sasso puts it “At the end of the day this serves as a reminder that we should get back to basics: keeping your body weight in check, being physically active, not smoking and following a good diet.”
• Single vitamins or high dose vitamins/antioxidants should not be advised to prevent prostate cancer (or any other cancer). Still it is very difficult to convince people not taking supplements.
• Another issue is that all kind of pharmaceutical companies keep on pushing the sales of these “natural products”, selectively referring to positive results only. It is about time to regulate this.

Sources & other reading (click on grey)

1. Huge disappointment: Selenium and Vitamin E fail to Prevent Prostate Cancer.(post on this blog about the SELECT trial)
2. Podcasts: Cochrane Library and MedlinePlus: (post on this blog)
   
3. Vitamins E and C in the Prevention of Prostate and Total Cancer in Men: The Physicians’ Health Study II Randomized Controlled Trial. J. Michael Gaziano et al JAMA. 2008;0(2008):2008862-11.[free full text]
   
4. 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 [free full text].
   
5. Randomized Trials of Antioxidant Supplementation for Cancer Prevention: First Bias, Now Chance-Next, Cause. Peter H. Gann JAMA. 2008;0(2008):2008863-2 [free full text].
   
6. Combined lycopene and vitamin E treatment suppresses the growth of PC-346C human prostate cancer cells in nude mice. Limpens J, Schröder FH, et al. J Nutr. 2006 May;136(5):1287-93 [free full text].
   
   News
   
7. The New York Times (2008/11/19) Study: Vitamins E and C Fail to Prevent Cancer in Men.
8. BBC news: (2008/12/10) Vitamins ‘do not cut cancer risk’.
9. The New York Times (2008/11/20) News keeps getting worse for vitamins.
10. The New York Times (2008/10/01) Vitamin C may interfere with cancer treatment.

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

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, both 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.

Vodpod videos no longer available.

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)
– 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 Best Study Design… For Dummies.

When I had those tired looks again, my mother in law recommended coenzyme Q, which research had proven to have wondrous effects on tiredness. Indeed many sites and magazines advocate this natural energy producing nutrient which mobilizes your mitochondria for cellular energy! Another time she asked me if I thought komkommerslank (cucumber pills for slimming) would work to loose some extra weight. She took my NO for granted.

It is often difficult to explain people that not all research is equally good, and that outcomes are not always equally “significant” (both statistically and clinically). It is even more difficult to understand “levels of evidence” and why we should even care. Pharmaceutical Industries (especially the supplement-selling ones) take advantage of this ignorance and are very successful in selling their stories and pills.

If properly conducted, the Randomized Controlled Trial (RCT) is the best study-design to examine the clinical efficacy of health interventions. An RCT is an experimental study where individuals who are similar at the beginning are randomly allocated to two or more treatment groups and the outcomes of the groups are compared after sufficient follow-up time. However an RCT may not always be feasible, because it may not be ethical or desirable to randomize people or to expose them to certain interventions.

Observational studies provide weaker empirical evidence, because the allocation of factors is not under control of the investigator, but “just happen” or are choosen (e.g. smoking). Of the observational studies, cohort studies provide stronger evidence than case control studies, because in cohort studies factors are measured before the outcome, whereas in case controls studies factors are measured after the outcome.

Most people find such a description of study types and levels of evidence too theoretical and not appealing.

Last year I was challenged to tell about how doctors search medical information (central theme = Google) for and here it comes…. “the Society of History and ICT”.

To explain the audience why it is important for clinicians to find ‘the best evidence’ and how methodological filters can be used to sift through the overwhelming amount of information in for instance PubMed, I had to introduce RCT’s and the levels of evidence. To explain it to them I used an example that stroke me when I first read about it.

I showed them the following slide :

And clarified: Beta-carotene is a vitamine in carrots and many other vegetables, but you can also buy it in pure form as pills. There is reason to believe that beta-carotene might help to prevent lung cancer in cigarette smokers. How do you think you can find out whether beta-carotene will have this effect?

• Suppose you have two neighbors, both heavy smokers of the same age, both males. The neighbor who doesn’t eat much vegetables gets lung cancer, but the neighbor who eats a lot of vegetables and is fond of carrots doesn’t. Do you think this provides good evidence that beta-carotene prevents lung cancer?
  There is a laughter in the room, so they don’t believe in n=1 experiments/case reports. (still how many people don’t think smoking does not necessarily do any harm because “their chainsmoking father reached his nineties in good health”).
  I show them the following slide with the lowest box only.
• O.k. What about this study? I’ve a group of lung cancer patients, who smoke(d) heavily. I ask them to fill in a questionnaire about their eating habits in the past and take a blood sample, and I do the same with a simlar group of smokers without cancer (controls). Analysis shows that smokers developing lung cancer eat much less beta-carotene containing vegetables and have lower bloodlevels of beta-carotene than the smokers not developing cancer. Does this mean that beta-carotene is preventing lung cancer?
  Humming in the audience, till one man says: “perhaps some people don’t remember exactly what they eat” and then several people object “that it is just an association” and “you do not yet know whether beta-carotene really causes this”. Right! I show the box patient-control studies.
• Than consider this study design. I follow a large cohort of ‘healthy’ heavy smokers and look at their eating habits (including use of supplements) and take regular blood samples. After a long follow-up some heavy smokers develop lung cancer whereas others don’t. Now it turns out that the group that did not develop lung cancer had significantly more beta-carotene in their blood and eat larger amount of beta-carotene containing food. What do you think about that then?
  Now the room is a bit quiet, there is some hesitation. Then someone says: “well it is more convincing” and finally the chair says: “but it may still not be the carrots, but something else in their food or they may just have other healthy living habits (including eating carrots). Cohort-study appears on the slide (What a perfect audience!)
• O.k. you’re not convinced that these study designs give conclusive evidence. How could we then establish that beta-carotene lowers the risk of lung cancer in heavy smokers? Suppose you really wanted to know, how do you set up such a study?
  Grinning. Someone says “by giving half of the smokers beta-carotene and the other half nothing”. “Or a placebo”, someone else says. Right! Randomized Controlled Trial is on top of the slide. And there is not much room left for another box, so we are there. I only add that the best way to do it is to do it double blinded.

Than I reveal that all this research has really been done. There have been numerous observational studies (case-control as well cohorts studies) showing a consistent negative correlation between the intake of beta-carotene and the development of lung cancer in heavy smokers. The same has been shown for vitamin E.

“Knowing that”, I asked the public: “Would you as a heavy smoker participate in a trial where you are randomly assigned to one of the following groups: 1. beta-carotene, 2. vitamin E, 3. both or 4. neither vitamin (placebo)?”

The recruitment fails. Some people say they don’t believe in supplements, others say that it would be far more effective if smokers quit smoking (laughter). Just 2 individuals said they would at least consider it. But they thought there was a snag in it and they were right. Such studies have been done, and did not give the expected positive results.
In the first large RCT (appr. 30,000 male smokers!), the ATBC Cancer Prevention Study, beta-carotene rather increased the incidence of lung cancer with 18 percent and overall mortality with 8 percent (although harmful effects faded after men stopped taking the pills). Similar results were obtained in the CARET-study, but not in a 3rd RCT, the Physician’s Health Trial, the only difference being that the latter trial was performed both with smokers ànd non-smokers.
It is now generally thought that cigarette smoke causes beta-carotene to breakdown in detrimental products, a process that can be halted by other anti-oxidants (normally present in food). Whether vitamins act positively (anti-oxidant) or negatively (pro-oxidant) depends very much on the dose and the situation and on whether there is a shortage of such supplements or not.

I found that this way of explaining study designs to well-educated layman was very effective and fun!
The take-home message is that no matter how reproducible the observational studies seem to indicate a certain effect, better evidence is obtained by randomized control trials. It also shows that scientists should be very prudent to translate observational findings directly in a particular lifestyle advice.

On the other hand, I wonder whether all hypotheses have to be tested in a costly RCT (the costs for the ATCB trial were $46 million). Shouldn’t there be very very solid grounds to start a prevention study with dietary supplements in healthy individuals ? Aren’t their any dangers? Personally I think we should be very restrictive about these chemopreventive studies. Till now most chemopreventive studies have not met the high expectations, anyway.
And what about coenzyme-Q and komkommerslank? Besides that I do not expect the evidence to be convincing, tiredness can obviously be best combated by rest and I already eat enough cucumbers…. 😉
To be continued…

SOURCES:
Clinical Studies and designs: several paper books; online e.g. GlossClinStudy on a vetenarian site
The ATCB study: The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-35. See free full text here
Overview of ATBC and CARET study 2 overwiews at www.cancer.gov, one about the ATBCfollowup and one about the CARET-trial
Overview of other RCT’s with surprising outcomes: on wikipedia

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Toen ik er weer eens donkere kringen onder mijn ogen had, raadde mijn schoonmoeder me coenzym Q aan, waarvan ze net gelezen had dat het een wetenschappelijk bewezen effectieve vermindering van vermoeidheid geeft. Inderdaad bevelen veel webpagina’s en huis-aan-huis bladen deze “natuurlijke en energie-mobiliserende voedingstof die je mitochondrien aanzet tot cellulaire energie” aan. Een andere keer vroeg ze me of ik dacht dat je wat pondjes zou kunnen kwijtraken door komkommerslank. Ze nam met een stellig NEE genoegen.

Het is vaak heel moeilijk duidelijk te maken dat niet alle research even goed is en niet alle uitkomsten even significant (zowel statistisch als klinisch). Nog moeilijker is het om de “bewijsniveau’s (levels of evidence)” uit de doeken te doen of om uit te leggen waarom je uberhaupt zoiets zou willen weten. De pharmacie en zeker de supplement verkopende bedrijfjes varen wel bij de goedgelovigheid van de gemiddelde consument. Hun verhalen en pillen vinden gretig aftrek.

Een gerandomiseerde gecontroleerde trial (RCT) is, indien goed uitgevoerd, het ‘beste’ studietype om aan te tonen of een behandeling werkzaam of nuttig is. Een RCT is een experimentele studie waarbij de deelnemers, die bij start van de studie vergelijkbaar zijn, door het lot worden toegewezen aan een (bepaalde) interventie- of controlegroep en waarbij na een bepaalde tijd de uitkomsten in beide groepen worden vergeleken. Een RCT is echter niet altijd haalbaar of wenselijk, bijvoorbeeld omdat het niet ethisch is om mensen te randomiseren of om hen bloot te stellen aan bepaalde interventies.

Observationele studies zijn zwakker in bewijskracht, omdat de toewijzing van de factoren niet in handen liggen van de onderzoeker, maar van het lot (natuur, werkomstandigheden, eigen keuzes). Van de observationele studies hebben cohort studies een hogere bewijskracht dan case control studies, omdat de te onderzoeken factoren bij cohort studies worden bepaald vòòrdat de uitkomst bekend is, terwijl dit bij case control studies juist gebeurt nadat de uitkomst bekend is.

De meeste mensen vinden zo’n beschrijving van studietypes the theoretisch en nietszeggend. Het spreekt ze niet aan, omdat ze zich er niets bij voor kunnen stellen.

Afgelopen jaar werd ik uitgedaagd om te vertellen “hoe artsen medische informatie zoeken” (het centrale thema was Google en informatie) voor …en nou komt-ie.. “De Vereniging voor Geschiedenis en Informatica”.

Om het publiek uit te leggen waarom het belangrijk is dat klinici de beste evidence vinden en hoe zij met behulp van methodologische filters het kaf van het koren kunnen scheiden, moest ik hen eerst uitleggen wat RCT’s en bewijsniveau’s zijn. Ik legde hen dit uit aan de hand van een onderwerp dat mij na aan het hart ligt.

Ik toonde hen een dia met daarop de vraag: Voorkomt bètacaroteen longkanker?
En ik legde hen uit dat bètacaroteen een vitamine is die veel in worteltjes en bepaalde andere groente voorkomt, maar die je ook als pillen kan slikken. Er zijn aanwijzingen dat bètacaroteen longkanker bij rokers zou helpen voorkomen. Hoe denkt u dat u dit het best kunt aantonen?

• Stel u heeft 2 buren, beiden kettingroker, man, en even oud. De buurman die weinig groente eet krijgt longkanker, maar de buurman die heel veel groente eet en gek is op worteltjes krijgt het niet. Kunnen we nu concluderen, dat bètacaroteen longkanker bij rokers voorkomt?
  Er wordt hartelijk gelachen, dus men gelooft hier niet in n=1 experimenten/case reports. (maar je moet ze maar de kost geven die denken dat roken geen kwaad kan omdat hun shaggies verslindende vader een taaie kerel was die nog tot op hoge leeftijd volop van het leven genoot).
  Ik toon hen een nieuwe slide met daarop het woord “casus”.
• O.k. Wat vind u hiervan? Er is een groep longkankerpatienten, die veel gerookt heeft. Ik vraag of de patienten een vragenlijst willen invullen en neem wat bloed af. Datzelfde doe ik met een vergelijkbare groep rokers die géén kanker ontwikkeld heeft. Ik analyseer alles en wat blijkt? In de groep met longkanker zitten vooral rokers met een minder caroteenrijk voedingspatroon en minder caroteen in hun bloed. Betekent dit dat bètacaroteen longkanker voorkomt?
  Geroezemoes. Iemand zegt: “misschien kunnen sommige mensen zich helemaal niet zo goed herinneren wat ze vroeger precies hebben gegeten”. Anderen werpen tegen “dat het alleen maar een associatie is” en “dat je niet zeker weet of het echt alleen de betacaroteen is die dit effect geeft.” Heel goed! Op het scherm verschijnt “patient-controle onderzoek”.
• Dan doe ik het anders. Ik volg een grote groep ‘gezonde’ zware rokers, ik volg hun eetgewoonten (inclusief het gebruik van supplementen) nauwgezet en neem regelmatig bloed af. Na lange tijd krijgen sommige rokers longkanker, maar andere niet. Nou blijkt wéér dat de groep die geen longkanker kreeg meer caroteenrijk voedsel at en meer betacaroteen in zijn bloed had. Wat denkt u hiervan?
  Het is een beetje stiller, je voelt de aarzeling, tot iemand zegt. “Nou, het overtuigt wel iets meer”. Een ander werpt tegen: “maar wie zegt dat het de worteltjes zijn, misschien is het wel iets anders in het eten of misschien is de levensstijl sowieso gezonder. Cohort-studie verschijnt op het scherm. Wat een perfect publiek, daar kan menig geneeskunde student nog een puntje aan zuigen.
• Ik begrijp dat u niet geheel overtuigd bent van de bewijskracht van deze studies. Maar hoe zou u dan vaststellen dat bètacaroteen de kans op longkanker verlaagt bij rokers? Stel dat u het echt zou willen weten, hoe zet u de studie dan op?
  Gegrinnik. Iemand zegt: “Geef de helft van de rokers beta-caroteen en de andere helft niets”. “Of een placebo”. zegt een ander. Prima! Er verschijnt “Randomized Controlled Trial” boven aan de slide. Er is geen ruimte meer over, dus we zijn er. Ik vertel alleen nog iets over het belang van dubbelblind onderzoek.

Dan onthul ik dat dergelijke onderzoeken ook werkelijk gedaan zijn. Uit tal van observationele (case-control en cohort) studies is gebleken dat er een omgekeerde relatie bestaat tussen inname van bètacaroteen en ontwikkelen van longkanker bij rokers. Hetzelfde geldt voor vitamine E.

“Nu u dat weet”, vraag ik het publiek “Zou u dan als kettingroker deelnemen aan een studie waar u random toegewezen wordt aan een van de volgende behandelingen:
1. bètacaroteen, 2. vitamine E, 3. beiden of 4. geen van beiden (placebo)?”

De inclusie faalt. Sommigen geloven niet in supplementen, anderen stellen dat het beter zou zijn als rokers stopten met roken (instemmend gelach). Twee mensen zeggen dat ze het in overweging zouden nemen. Maar men vermoed (gezien het voorafgaande) een addertje onder het gras en ze hebben gelijk. Dergelijke studies zijn gedaan en hebben niet het gewenste resultaat opgeleverd.
In de eerste grote RCT (ca. 30.000 mannelijke rokers!), de ATBC Cancer Prevention Study, verhoogde bètacaroteen juist het aantal longkankergevallen met 18% en de algehele sterfte met 8% (hoewel het effect langzaam uitdooft als mensen met de pillen stoppen). Vergelijkbare resultaten werden verkregen in de CARET-studie, maar niet in een 3e RCT, de Physician’s Health Trial, die ook niet-rokers had geincludeerd.
Aangenomen wordt nu dat sigaretterook bètacaroteen afbreekt tot gevaarlijke afvalproducten, een proces dat gekeerd kan worden door andere oxidanten (normaal aanwezig in het voedsel). Of vitaminen een positieve (anti-oxidant) of negatieve (pro-oxidant) werking hebben hangt erg af van de dosis, de vorm, en de situatie: vitamines in fysiologische concentraties zijn met name nuttig bij een tekort eraan.

Deze manier van studietypes uitleggen aan goed-ontwikkelde leken vond ik erg effectief en leuk om te doen bovendien.

De boodschap is dat hoezeer observationele studies ook op een bepaald effect wijzen, beter evidence verkregen kan worden met een RCT (hoewel dit niet altijd kan en mag). Het laat ook zien dat je als wetenschapper (en dokter) heel voorzichtig moet zijn met het direct vertalen van ‘waarnemingen’ naar adviezen richting een bepaalde therapie of levensstijl.

Aan de andere kant vraag ik me wel af, of alle hypothesen getest moeten worden in een overigens zeer kostbare RCT (kosten van de ATCB trial bedroegen $46 miljoen). Zou er niet een heel stevige basis moeten zijn vòòr je een preventieve studie doet met supplementen bij gezonde individuen? Zijn er geen risico’s ? Zelf denk ik dat we heel terughoudend moeten zijn met chemopreventie studies. Tot op heden hebben ze trouwens niet aan de hoge verachtingen voldaan.
Wat coenzym-Q en komkommerslank betreft? Behalve dat ik er gewoon niet in geloof (ik bedoel dat er evidence bestaat dat ze werken), denk ik dat vermoeidheid het best bestreden kan worden met rust en ik eet zat komkommers. 😉 Volgende keer meer…..

A really delicious blog …

If you like food, blogging, excellent photography, recipes, information about Munich and Web technology and tools including WordPress plugins, than don’t miss delicious days.

In “about” you can read that “delicious days” is made by a passionate German couple in Munich.
She loves to cook and has a job in the design and internet business world and he learned to enjoy cooking and is the technical genius behind the site.

The blog is beautifully designed. Look for instance at the Gallery, with perfect photo’s sorted by category. After you have choosen a particular photo you can move to the next or previous ones or press the play button.

In the recipe-list you can get an idea of the recipe by pressing the “preview”-button, while remaining in the list.

Why do I refer to this blog here? I like food, that’s for sure, (I even have a web page on a dutch food web site, smulweb), but I came here while following a link from bakkel dot com (once again) to http://www.deliciousdays.com/cforms-plugin, which is in fact one part of the plugin pages/tabs at delicious days. You’re free to share these plug-ins.

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Als je gek op lekker eten bent, recepten, blogging, mooie foto’s, en geinteresseerd in web 2.0 trucjes zoals wordpress plugins neem dan eens een kijkje op de food blog delicious days.

Delicious days wordt gerund door een duits stel, waarvan zij de de liefde voor het eten heeft ingebracht en via haar werk kennis heeft van design en internet business, en hij de technische inbreng verzorgt. Een ideale mix.

Delicious days is een WordPress blog, maar zo aangepast in stijl dat dat niet direct opvalt. Het zit heel vernuftig in elkaar. In the Gallery kun je foto’s in een categorie individueel bekijken of in serie afspelen. In de receptenlijst kun je eerst een indruk krijgen van het recept door op “preview” te klikken, waardoor er een stijlvolle pop-up tevoorschijn komt. De wordpress-plugins die ze met je willen delen staan op een aparte pluginpagina.

Waarom ik op deze blog terecht kwam? Ik ben zelf een liefhebber van eten en ben geinteresseerd in voedsel in bredere zin; ik heb zelfs een eigen webpagina op smulweb), maar ik kwam toevallig op deze site door (wederom) een link te volgen via bakkel dot com naar cforms-plugin op deze site. Ook weet ik dat enkele spoetnikers zoals Moira geinteresseerd zijn in eten en aan een Google-doc over dit onderwerp hebben samengewerkt (ik weet uit mijn hoofd niet meer wie). Misschien hebben ze hier wat aan. Tevens zullen sommigen die graag zelf hun wordpress willen (gaan) hosten misschien wat hebben aan de tips en de plug-ins. Anderen zullen kunnen genieten van de foto’s.