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OT: RCT Vitamin D PLUS calcium NOT significant help against all type cancer in older women ?

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Posted 8/29/2018 10:36 PM (GMT -5)
So here is another RCT showing all type cancers were NOT significantly reduced over 4 years of supplementation. The groups mean vitamin D was already pretty good at 32.8 ng/mL at the start of the study. The intervention women were given 2000/day vit D plus 1500 mg/d of calcium. A new diagnosis of cancer was confirmed in 109 participants, 45 (3.89%) in the vitamin D3 + calcium group and 64 (5.58%) in the placebo group (difference, 1.69% [95% CI, −0.06% to 3.46%]; P = .06). Kaplan-Meier incidence over 4 years was 0.042 (95% CI, 0.032 to 0.056) in the vitamin D3 + calcium group and 0.060 (95% CI, 0.048 to 0.076) in the placebo group; P = .06. In unadjusted Cox proportional hazards regression, the hazard ratio was 0.70 (95% CI, 0.47 to 1.02). Adverse events potentially related to the study included renal calculi (16 participants in the vitamin D3 + calcium group and 10 in the placebo group), and elevated serum calcium levels (6 in the vitamin D3 + calcium group and 2 in the placebo group).

Though the # of cancers were lower and hazard ratios(.7) were lower in the vitamin D/calcium group, they were deemed insignificant. ( or were they? different details at the end of the study)

Somebody said...
Conclusions and Relevance Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years. Further research is necessary to assess the possible role of vitamin D in cancer prevention.........................
Participants were asked to limit vitamin D supplementation, outside of the intervention, to 800 IU per day, in keeping with the National Academy of Medicine (NAM; formerly Institute of Medicine) recommended intake level.16 Participants also were asked by study nurses to limit additional calcium to 1500 mg per day as directed by the investigators and DSMB to be consistent with the previous Creighton cancer and vitamin D study..........................



So the placebo group may have also been getting some vitamin D? I notice the mean baseline for both groups, at almost 33, was above what most people usually have, unless they supplement.


Somebody said...
Mean outside-of-study vitamin D3 and calcium supplement dose for visits 2 through 9 in each group are reported in Table 2, as are dietary intakes for each nutrient. No differences were observed, except in vitamin D supplementation: women in the placebo group took higher amounts of vitamin D supplementation in addition to the study supplements than those in the vitamin D3 + calcium group.



Sigh. That seems to dilute the results a bit, if the gals in the placebo were actually taking their own vitamin D. Even though the HR was lower in the intervention group, wouldn't it possibly have been even lower if the "placebo" group were not taking their own vitamin D? Sigh. Frustrating. Still, at 4 years I notice (in the table 3 )I notice 16 breast cancers in the vit D/calcium group, but 23 in the "placebo" group, who were also getting some vitamin D outside the study on their own. That is 43% more breast cancers. But apparently that is not significant?

But, I guess they were just looking at total cancers of all types, which was 45 total for the intervention and 64 total in the so called placebo. Still, that is 42% more cancers in the placebo group, even though they were also getting some vitamin D. But, again, apparently insignificant?

Somebody said...
With age adjustment, the HR associated with treatment was 0.70 (95% CI, 0.48 to 1.02). With adjustment for estrogen agonist and antagonist use, the HR was 0.70

Somebody said...
There were no serious supplement-related adverse events............

Aha. You have to dig to find these things. Near the end, I see this:

Somebody said...

Post Hoc Analyses

In post hoc analysis, in which participants who withdrew, died, or developed cancer prior to being in the study for 12 months were excluded (excluding 84 participants in the vitamin D3 + calcium group and 78 in the placebo group), a total of 34 participants in the vitamin D3 + calcium group and 52 participants in the placebo group developed cancer during years 2 through 4 (χ2, 3.17% vs 4.86%, P = .046); difference in proportions, 1.7% (95% CI, 0.1% to 3.4%). In Kaplan-Meier analysis, the difference was significant (log-rank test of equality over strata, P = .047), and in proportional hazards modeling, the HR was 0.65 (95% CI, 0.42 to 0.99) (eFigure 1

So once getting rid of the folks who probably already had cancer when the study started, then IT WAS SIGNIFICANT? WTH? Why isn't that the headline? One could get the impression that there are some things that some people just don't want you to know. WTH? But that is not all:

Somebody said...
In another post hoc analysis, the achieved serum 25(OH)D level was significantly inversely associated with cancer incidence (P = .03, coefficient, −0.017). Compared with 25(OH)D level of 30 ng/mL as baseline, the estimated HR for cancer incidence for 25(OH)D levels between 30 ng/mL and 55 ng/mL was 0.65

Sigh. So the higher the value of vitamin D, the lower the cancer, and the difference is significant, and that is not the headline? The hazard ratio comparing an already quite good 30 ng/ml vs 55 was a freaking .65? If they had a drug or a treatment that that had low SEs and offered a hazard ratio of .65, and cost thousands of $ per year, are you telling me they would not headline that on TV nightly news? (maybe not if it was dirt cheap)

I started out trying to be a good boy and report the evidence however it might fall. Evidence that seemed to be against my usual argument. But the further I dug into the details, the more I realized their 1st listed conclusion(no significant benefit) is BOGUS. Plus it is a bad study with the so called placebo also taking vitamin D. But STILL, the intervention group had LESS cancer, and the higher the blood level of vitamin D the better. I'm telling you, you just can not trust studies, especially if you do not dig into the details. FRUSTRATING! ( and yet once again, they are not comparing against a placebo, but simply against a lower- but maybe adequate- dose of vitamin D. FRUSTRATING!

/jamanetwork.com/journals/jama/fullarticle/2613159?widget=personalizedcontent&previousarticle=2607813#joi170019t2

Post Edited (BillyBob@388) : 8/30/2018 7:59:16 AM (GMT-6)

Posted 8/29/2018 10:51 PM (GMT -5)
From the discussion:

Somebody said...
One explanation for lack of statistically significant differences between the treatment groups in all-type cancer incidence is that the study cohort had higher baseline serum 25(OH)D levels compared with the US population. In the US National Health and Nutrition Examination Surveys (NHANES) from 2001 through 2006, an estimated 75% to 80% of the adult population had serum 25(OH)D level values less than 30 ng/mL, and approximately 30% had 25(OH)D level values below 20 ng/mL

Yep. That's what I said, that raised a question for me. But still they got better #s for the vitamin D intervention group.

Somebody said...
The higher intake of outside vitamin D3 supplementation in the placebo group in this study cohort (the majority of individuals would be considered to be vitamin D sufficient23) might obscure any treatment effect in the intention-to-treat analysis.

Yep, that is what I said. So why headline that your trial shows no significant benefit?

Somebody said...
The association observed in the post hoc analysis excluding cancers that were diagnosed during year 1 may be related to the possibility that cancers diagnosed early in the study may have been present upon enrollment and that time is needed for vitamin D supplementation to increase serum 25(OH)D level and to exert a potential effect on cancer development or progression. However, this finding, as well as the post hoc observation suggesting an inverse association between serum 25(OH)D levels and cancer, should be considered only exploratory and hypothesis generating, and require assessment in further studies.


Well, if they say so, I guess.
Posted 8/29/2018 10:54 PM (GMT -5)

Somebody said...
This study also has several limitations. The cohort included older women, primarily non-Hispanic white, and no men, which limits generalizability.

Allowing members of the placebo group to take their own vitamin D and calcium, not to exceed NAM recommendations, may have biased the analyses by treatment group toward null.

The NAM recommendations for minimum vitamin D intake and of 25(OH)D level for skeletal health, and the high prevalence of low vitamin D status and osteoporosis rendered it unethical to ask participants to avoid any supplemental vitamin D and calcium. Furthermore, due to widespread information about the potential importance of vitamin D, it would be unfeasible to recruit for a large study in which no participants were permitted to take vitamin D. Sample-size calculations were based on a study cohort with lower baseline 25(OH)D levels than the current cohort and limited the power to find an effect of vitamin D3 supplementation. Another limitation was the post hoc nature of the analysis that excluded cancers diagnosed during year 1 and the analysis that examined the relationship between 25(OH)D levels and cancer.
Conclusions

Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years. Further research is necessary to assess the possible role of vitamin D in cancer prevention.

Posted 8/30/2018 2:55 PM (GMT -5)

Somebody said...
Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years.

After reading deeper into the study, I do not at all agree with their conclusion. Thoughts? Now, true, they do not consider the results "significant" until they adjust for the women who probably already had an undiagnosed cancer at the start of the study. Plus, their qualifier "women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL" shows that it is a tainted study to begin with, as the average participant was obviously already supplementing. So at best they prove that- yet again - that people who are already supplementing do not get "significant" improvement with additional supplementation.

Regardless of all of that, they did indeed get a 30 or 40% improvement, but it is not deemed significant. However, when they adjust for the above flaws, and remove those who already had a cancer, or adjust for the ones with the highest vs lowest vitamin D levels(adjust for either), even they must admit the differences are now significant. With a very significant further improvement when going from the 33 ng/ml level to the 50s. But they totally down play those aspects, leaving the impression there was no benefit from supplementation.

My main disagreement with their conclusion is with "supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk". This was in no way a true placebo controlled study. Both groups were already supplementing, and the "control group", that was given the placebo, was allowed to keep on supplementing. And who knows how much the were actually taking? But what kind of results would they get if they were comparing to a group with 25 or 20 or 15 ng/ml? That is what I want to know. And there are plenty of folks around in those categories. Or, at least there were before so many people began supplementing.

They said they did not prevent the control group from doing their own supplementation because it would be unethical to with hold vitamin D from them. Why would it be unethical?

Post Edited (BillyBob@388) : 8/30/2018 2:01:32 PM (GMT-6)

Posted 8/30/2018 4:36 PM (GMT -5)
There you go again, mixing up the forums you visit. Looks like you meant to post this one in your forum for old women with cancer.
Posted 8/31/2018 9:37 AM (GMT -5)

Normal59 said...
There you go again, mixing up the forums you visit. Looks like you meant to post this one in your forum for old women with cancer.

Good and helpul response there, Normal. I am amazed at how quickly a thread can deteriorate. This was an OT post, something that is done quite often here, by a lot of people. But I guess you have no interest in the subject of cancer in women or cancer general? If so, I'm sorry I bothered you.

Since you bothered to comment- and I thank you for doing so- how about a not sarcastic comment about your thoughts on the results of the actual study? Do you think that, despite the authors conclusion and flaws that wold prevent a benefit from being detected, it actually showed a benefit in various cancers for these women, like 1/3 fewer? Or not? Admittedly, these women cannot get prostate cancer, so this may or may well not apply to us. However, this is at least the second recent RCT to show benefits for vitamin D supplementation in a wide variety of other cancers.

So I'd be interested in your thoughts as to why even such a flawed Study(placebo-controlled Group which has a high baseline vitamin D level and is allowed to continue with their own supplementation during the trial) still managed to show lower cancer rates with the additional vitamin D of the intervention group. And indeed, significant differences when adjusting for either probable pre-existing cancers or when adjusted for adequate(high normal) Vitamin D levels versus the very highest vitamin D levels(over 50). With the highest levels showing another impressive, significant improvement compared to levels closer to 30. Any thoughts on that?

I'd also be interested in your (or any one else) thoughts on why the obviously positive results are not at least equally emphasized in the conclusion for this study, rather than the" no significant benefit" part. Which though that might be technically correct - when comparing to Women who already have a higher than average vitamin D level to start with, and are allowed to supplement vitamin D on their own–while technically correct, a conclusion of "oh yes there was improvement, but not significant" still seems to miss some vital information.

To me it seems as though they simply did not want to hear or report the results of this study. I think there's plenty of people like that. This reminds me of the studies of high vitamin D versus really high vitamin D not showing a significant difference in colds, with the results reported almost ignoring the fine print that says there was a 50% improvement in flu rates. Even though they started with more than adequate doses of vitamin D in the so-called control group. (can't help but wonder–in any of these studies– what the results would be when compared to people not supplementing at all and/or with the typical low levels– Well below 25 or 20–that most non-supplementing people I have)

This is now at least the second RCT to show significant improvements in a wide variety of cancers in women supplemented with daily oral vitamin D. And at least a second RCT to show significant improvements when vitamin D blood levels increase above the already above average 30, 40 and even 50 ng/ml. But for some reason plenty of people just do not want to hear such news, apparently. And for some reason they keep doing these studies on women far more than men. We only have one RCT(That I know of) for prostate cancer, with men being given one massive dose of vitamin D once a month, and that of course showed no benefit(Though also showed no harm).

But if you have some thoughts on any of the above, maybe something other than how I have once again posted on the wrong forum, I would really love to hear them. Really.
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