Moss Report july 6th 2008
Posted by Jonathan Chamberlain on July 7, 2008
For July 6, 2008
WHAT’S IN A WORD?
I have been slogging through the latest study attacking the concurrent use of antioxidants during cancer therapy. This study is titled “Should Supplemental Antioxidant Administration Be Avoided During Chemotherapy and Radiation Therapy?” It appeared June 4, 2008 in the Journal of the National Cancer Institute (Lawenda 2008). The paper is a review: that is, it does not contain any new data but is a commentary on data that already exists. What makes it a bit newsworthy is that some of the authors are tangentially related to the complementary and alternative field.
But as I was working my way through the article I came upon a most unusual paragraph. The authors were discussing a now-famous study of the use of synthetic antioxidants during radiation therapy. The official title of this study was “Beta-Carotene and Alpha-Tocopherol Chemoprevention of Second Primary Malignancies in Head and Neck Cancer Patients.” It took place at Laval University in Quebec, Canada, and was sponsored by the National Cancer Institute of Canada (NCIC). The first author was Isabelle Bairati, MD, PhD, and so this is sometimes called the Bairati study. But I will refer to it here as the Laval study. The study began in October 1994 and the first results were announced in April 2005-thus it took over a decade to complete.
The results were decidedly mixed. The administration of synthetic beta-carotene and alpha-tocopherol during cancer treatment did result in a 38 percent decrease in severe side effects. However, there also appeared to be a reduction of 29 percent in local tumor control for the alpha tocopherol group and a 56 percent reduction in tumor control in the group that received both alpha tocopherol and beta-carotene. Since this was among the few large randomized clinical trials (RCTs) examining the use of antioxidants during radiation therapy, it provided ammunition to those who advocate that one should entirely avoid the use of supplemental antioxidants during cancer therapy, at least until there is further good RCT data.
However, in 2008 the Laval authors issued a bombshell. In a further analysis, they showed that the harmful effect of these synthetic vitamins was entirely restricted to one group – smokers. And not just smokers, but those who smoked through the course of their radiation therapy. All other groups appeared to be unharmed by the interaction.
There was another paper from the same group of researchers with even more surprising findings. This study found that participants who had the highest dietary intake of beta carotene had a 39 percent reduction in severe adverse effects (which was statistically significant). There was a similar trend with alpha tocopherol (albeit not statistically significant). More encouragingly, “participants with higher plasma beta carotene had a significantly lower rate of local recurrence.” There was 33 percent reduction in the cancer recurrence rate. Alpha tocopherol was not related to severe adverse effects or to cancer recurrence. But the intake of the antioxidant beta-carotene through dietary sources appeared to be a win-win situation. The problem that was earlier reported appeared to be in the manufacture of the synthetic beta carotene supplements used in the study.
Carotene is an orange pigment that is important for plant photosynthesis. The main dietary sources are the orange and yellow fruits and vegetables, including (as the name suggests) carrots, but also sweet potatoes, mangoes and cantaloupe. Carotenes also lurk in many green leafy vegetables, such spinach, kale and chard. Beta-carotene is the most abundant and best known of the carotenes, but it almost always occurs in nature accompanied by its less known siblings, alpha gamma, delta and epsilon carotenes. In addition, in nature, carotenes are also often found alongside other natural food pigments such as xanthophylls, anthocynanins, and chlorophylls. Thus, when one assesses patients for their intake of “beta-carotene,” one cannot be sure that any perceived effect is not also due to one of these other substances, or (most likely) to a combination of these substances.
For reasons of scientific accuracy, however, the Laval authors only gave the patients in their clinical trial a synthetic form of pure beta-carotene. Although this decreased the adverse effects of radiation by a similar amount as did the increased dietary intake of natural beta carotene, it also led to the surprising increase in cancer recurrences. It is unknown, and a matter of speculation, whether this increase was due (a) to the synthetic nature of the vitamin (or possibly one of its additives or excipients) or (b) the lack of the other accompanying natural chemicals, as mentioned above.
In 2008, in a subgroup analysis of the previous data, the Laval authors showed that the harmful effects of radiation and synthetic beta-carotene (or alpha-tocopherol) were limited to those patients who continued to smoke during the course of their radiation therapy. Apparently there was something unique about the interaction of these synthetic antioxidants and tobacco metabolites that was particularly dangerous.
This observation was not surprising, but was fully in line with two earlier studies called the ATBC and CARET studies, dating from the 1990s. To quote the US National Cancer Institute:
To summarize, there were three major findings that came out of the Laval study:
Now let’s look at how Lawenda et al. report the Laval data in the JNCI.
First, they correctly recapitulate the benefit that the two synthetic antioxidants had on severe side effects. They also note that the Laval authors initially reported that the benefit was “offset by reductions in the local tumor control rate.”
Second, they report as “interesting” the finding that this harmful effect was limited to smokers. “There was no increase in either of these outcome measures for the nonsmokers,” they state. This seems pretty clear-cut.
So, in 2005, the Laval authors implied that the harmful effect was seen in the general patient population. In 2007, they reported that the ingestion of beta-carotene in foods was protective against side effects and not harmful in terms of recurrence. And in 2008, they modified their stance further and reported that the harmful effect was only seen in a subgroup of patients who continued to smoke during the course of their radiation therapy-a finding that was fully in line with the well-publicized ATBC and CARET studies. This finding would lead to the obvious conclusion that synthetic beta-carotene supplements should not be taken by smokers while they are undergoing radiation.
So far, there would seem to be little to argue with. However, at this point, the JNCI authors veered off course. They stated as follows:
Read this over. Based on the words “subsequent publication,” wouldn’t you think that after their findings that essentially exonerated beta carotene except in the case of active smokers the Bairati group next came up with some new finding that those patients “who received antioxidants” had a worse outcome? Isn’t that the logical inference from the word “subsequent”? (My dictionary defines “subsequent” as “following in time or order,” “coming after something else,” etc.)
According to the JNCI authors, however, subsequent does not mean…well, subsequent. It actually means the opposite. How is that? Because the “subsequent” study in question – their reference #17 – was actually published in 2006, whereas the earlier “interesting” study on smokers was published in 2008 – two years later!
Confused, I wrote to the lead author, Brian D. Lawenda, MD, who was kind enough to promptly reply to my inquiry. Here is what he wrote concerning the chronology of these studies: “The sequence of the presentation of this data (and the word ‘subsequent’) may be confusing to some readers, but the references clearly indicate the order of the trials.”
I had suggested to Dr. Lawenda that he and his coauthors issue a correction in the JNCI concerning their use of the word “subsequent.” But apparently none is needed since the correct order of events can (he says) be inferred from the references!
This sort of reasoning – in which sooner is later, and later sooner — leads to some interesting hypothetical situations. Here for example is my abbreviated History of World War II:
2) The Allies land in Normandy and proceed to subdue Germany.
3) Subsequently, Hitler launches a counter offensive at the Battle of the Bulge.
Apparently, as long as I provide properly dated footnotes I’m correct in my new history of the war in Europe. One can in fact change the entire history of the world to one’s liking using this new system of logic.
There is a lot more to say about this Lawenda et al. study and I hope to get to it soon. But I think the take away message for patients is as follows:
Incidentally, the JNCI authors seem aware of the difference between synthetic and natural forms of antioxidants (i.e., that beta carotene and alpha tocopherol in their dietary form are beneficial and not at all harmful) yet they ignore this critical part of the Laval work. But this is arguably the most important take away message.
Patients can get an enormous amount of beta-carotene safely through foods and there really is no need for synthetic antioxidants at all. One way of doing this is by juicing carrots – one pound normally yields about one 8 oz glass of juice. You can add other fruits or vegetables to the hopper to receive a broader spectrum of natural antioxidants. Patients should make sure to use organic carrots and wash them well. If one’s doctor has concerns about possible bacterial contamination of raw carrots (a potential problem for those with compromised immune systems) then one should try using steamed carrots. I have heard it said that gently steamed carrots have five times as much available beta-carotene than raw. Either way, if you do this consistently, you will raise your blood levels of beta-carotene into the highest percentile. A further benefit is that most oncologists, who routinely object to their patients taking any kind of food supplements, might feel silly telling them that they can’t eat a serving of steamed carrots.