Clinical trials Complementary and alternative medicine Medicine

Now that’s the way you do it!

i-e7a12c3d2598161273c9ed31d61fe694-ClassicInsolence.jpgDue to a death in the family, I have to go back into the vaults of the old blog for some more reruns. Regular blogging should resume in a day or two This particular post first appeared on June 16, 2005.

One of the overarching themes of this blog has been skepticism in the claims of alternative medicine. Consequently, a recurring type of post has been the debunking of some claim or other made by the proponents of alternative medicine. Sometimes debunking these claims is like shooting fish in a barrel, allowing for humorous play with the concept, and sometimes the claims are a bit harder to debunk, requiring a more serious approach. In the end, however, the vast majority of altie claims turn out to be without a solid basis in science and without evidence of efficacy if you look at them with a critical eye. From these posts, some conclude that I’m hoplessly hostile and biased against alternative medicine, but such is not the case at all. I merely insist that the claims of alternative medicine advocates be subjected to the same scientific standards as conventional medicine .

It is not at all uncommon for cancer patients to ask if there are any dietary manipulations that will treat their cancer. My stock response is usually that, although there is evidence for the efficacy of various dietary manipulations in reducing one’s risk of cancer, there is little or no good evidence that dietary manipulations will treat a cancer once it’s become established. By the time a patient develops a detectable cancer requiring treatment, the horse has left the barn a long time ago, so to speak. Consequently, other than making sure one eats a standard good diet with adequate calories, lots of fruits and vegetables, low fat, high fiber, etc., there are no known specific diets that will improve a cancer patient’s chances of beating the disease, at least none with any good evidence to support it. However, a recent study out of the Princess Margaret Hospital Cancer Center and the Massachusetts General Hospital Cancer Center may provide the basis for suggesting one dietary manipulation that might ultimately be useful in treating breast cancer, if subsequent studies pan out.

It has been known for a while that lignans have antiestrogenic properties, and blocking estrogen has been the mainstay of breast cancer treatment for estrogen receptor-positive tumors for decades. There are also preclinical studies indicating that lignans may have antitumor properties. It turns out that flaxseed is one of the richest sources of mammalian lignan precursors such as secoisolariciresinol diglucoside (SDG). These lignan precursors are converted by the bacteria in the colon into enterodiol (ED) and enterolactone (EL), the active lignans as shown below:

04-2326 3828..3835

There is also preclinical evidence that putting flaxseed in the diet can inhibit the growth of tumors in mice and even potentiate the efficacy of the estrogen blocker Tamoxifen. Based on this, the investigators decided to test whether this might be true in humans; so they designed a clinical trial, and you’re going to love how they did it. First off (this isn’t the part you’re going to love, but it has to be described), they designed the trial the same way many neoadjuvant therapy trials. Thirty-two postmenopausal women with a needle biopsy-proven cancer were randomized to two groups, one of which would receive the treatment and the other the placebo for 30-40 days prior to definitive surgery, with measurements of tumor markers of aggressiveness measured in the first pretreatment biopsy and then again in the definitive resection. Note that this is the sort of study that could only be done in a country with a national health care system. In the U.S., it would be difficult indeed to persuade women recently diagnosed with to wait 30-40 days for their definitive surgery. In Canada, though, that’s the usual waiting time; so the investigators could quite reasonably use the argument that their therapy was not unduly delaying definitive surgery.

Now here’s the part you’re going to love. The way they decided to administer flaxseed or placebo was to bake it into muffins that women were to eat every day. From the Methods section of the paper:

Study muffins. Study muffins were prepared in the standard manner by Canada Bread Co. (Toronto, ON, Canada). They contained similar ingredients and were prepared to contain 20.7 g white wheat flour for flaxseed muffins or 20.7 g whole-wheat flour for placebo muffins. Flaxseed muffins contained 25 g ground flaxseed. Placebo muffins were prepared with whole-wheat flour instead of white wheat flour to raise the dietary fiber content closer to that of the flaxseed muffins. All muffins were formulated to be isocaloric and equivalent in fat, protein, and dietary fiber. Hence additional canola oil (10 g) was added to placebo muffins but not to the flaxseed muffins. Muffins were also flavored with nutmeg, cinnamon, and vanilla extract to help maintain subject blindness. All flaxseed came from the same source (Omega Products, Melfort, Saskatchewan, Canada) and batch, and contained 2 mg of secoisolariciresinol diglucoside per gram. The patients kept their weekly supply of muffins at 20° C and defrosted them as needed. They ate one muffin per day at breakfast time. Any uneaten muffins or portions thereof were returned and weighed. The total intake of flaxseed was estimated as 25 g X treatment days – uneaten amounts.

I can assure you that I’ve never seen a section in a Methods section of a scientific paper entitled “Study Muffins” before. My partners and I were discussing this article at journal club and we couldn’t help but have a healthy chuckle and make all sorts of jokes about “studmuffins” and “magic muffins.” It didn’t help that the first sentence in the Results section read:

Muffin intake compliance was good (95.4% in the placebo and 92.5% in the flaxseed group) and did not differ significantly between the groups.

“Muffin intake compliance”? I love it. I can’t help but wonder if the investigators had a sense of humor and did that on purpose, knowing how it would sound.

All kidding aside, though, this was a pretty well-designed prospective randomized, double-blind, placebo-controlled pilot trial to look at what effect consuming flaxseed oil had on tumor markers in breast cancer. They measured urinary lignan excretion to show that it went up in the experimental group, meaning that lignans were being made, and they controlled for caloric and micronutrient intake between groups. What they found is as follows:

  1. A marker of tumor cell proliferation (Ki-67) decreased by 34.7% in the tumors in the experimental group compared to the control. Ki-67 reduction has been shown to be a pretty good surrogate endpoint biomarker for the efficacy of hormonal therapy in breast cancer. It is thought, but not yet proven mechanistically, that the mechanism of action of lignans is antiestrogenic. Given that estrogen-receptor tumors also demonstrated a reduction in Ki-67, it is clear that antiestrogenic effects alone cannot explain the action of flaxseed, and there are a number of hypotheses as to the mechanism of action of flaxseed.
  2. The c-erbB2 score (another marker of tumor cell proliferation and aggressiveness based on scoring the expression of the oncogene Her-2/neu, which is another name for c-erbB2) decreased by 71% in the control group compared to the control.
  3. Tumor cell apoptosis (programmed cell death) increased by 30.7% in the experimental group but remained the same in the control.

The amazing thing about these results is that, while the changes in the biomarkers caused by flaxseed are small compared to those induced by Tamoxifen in other trials of neoadjuvant therapy done over a similar timeframe, they are not that much smaller. Also, flaxseed is a dietary manipulation without major side effects, which might make it more attractive than Tamoxifen or other newer antiestrogen drugs in patients who are at high risk for side effects from such drugs. If flaxseed has efficacy in inhibiting breast cancer growth that is only, say 75%, of that of Tamoxifen with minimal side effects, it still might be worthwhile in some patients. Indeed, the investigators noted no side effects other than this:

The only side effects reported by subjects were increased abdominal fullness and bowel movements due to the high fiber content of flaxseed. As an increase in bowel movement may be desirable for patients with low fiber intake and chronic constipation, this effect may not be considered adverse compared to other side effects seen with breast cancer drugs such as tamoxifen or aromatase inhibitors.

So, does this mean postmenopausal women with breast cancer should toss their Tamoxifen or Arimidex into the trash and start making flaxseed muffins? Absolutely not. Not on the basis of this small unconfirmed trial, it doesn’t. This study needs to be confirmed in a larger number of women over a longer treatment period of time with definitive demonstration of actual tumor shrinkage. Biomarkers do not always correlate with antitumor response. The more likely implication of this study is that this dietary manipulation might have utility as a strategy for breast cancer prevention, either in lieu of long term Tamoxifen or Arimidex or as an adjunct. There is also the problem of standardization common to herbal remedies or natural substance remedies like flaxseed that can make it difficult to make sure that every lot of flaxseed has the the same amount of active ingredient.

Another important implication of this study is that, contrary to what some alties will tell you, it is possible to evaluate alternative medical claims in well-designed, well-controlled scientific studies. As I have pointed out before, the vast majority of these claims will not stand up to the light of careful scientific scrutiny, but it is possible that, in this one case, one claim for one alternative medicine intervention will.

And this is the way you start to do find out which of these claims might have something behind them.

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

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