The Vitamin C Empire Strikes Back

Well that didn’t take long, did it?

Three days ago, I described a study that I had noticed in the October 1 issue of Cancer Research that described an animal study that strongly suggested that vitamin C administered at sufficiently high doses may interfere with the action of multiple chemotherapeutic agents. You can read the link for full details of the study as discussed by yours truly. In fact, although I only blog sporadically about the exaggerated claims of advocates of vitamin C as a cancer cure, but when I do I like to think I hit the mark, starting two and a half years ago when I wrote about a couple of studies that were then making the rounds as “evidence” for the efficacy of vitamin C as a cancer treatment (one was weak evidence; one was hardly evidence at all); continuing to another study that claimed that mega-high dose vitamin C can cause tumor shrinkage in rodent models (it could, but the shrinkage was unimpressive and required enormous doses, the proverbial “long run for a short slide,” as I put it); and finally earlier this week the most recent study that demonstrated that vitamin C supplementation may not be such a good idea if you’re undergoing chemotherapy. Taken together, these posts constitute what I now dub my “Trilogy of Terror” with respect to vitamin C.

Not surprisingly, true believers in Linus Pauling’s view that vitamin C is some sort of panacea (or at least a cancer cure) were very quick to point to the studies encompassed by the first two posts in of my Vitamin C Trilogy of Terror as vindication of the great Nobel Prize winner turned crank, because, no matter how weak the evidence or results were, they still were seemingly positive results suggesting that vitamin C may actually have a beneficial effect against cancer, no matter how wimpy.

They aren’t at all pleased about the most recent study, though. No, they’re not happy at all that there is evidence in an animal model that vitamin C may interfere with chemotherapy. I just knew that sooner or later a vitamin C crank would attack the study. I just didn’t know it would be Linus Pauling’s bastard stepchild itself, Orthomolecular.org, and I failed to guess just how woo-filled the counterattack would be. It came in the form of a press release entitled Chemotherapy doesn’t work, so blame vitamin C.

My neurons are having to activate their cell survival pathways to fight off a massive wave of stupidity-induced apoptosis as we speak. Check out what I mean:

OMNS, October 7, 2008) When Memorial Sloan-Kettering Cancer Center announces that vitamin C may interfere with chemotherapy, the news media trumpet it far and wide. But before cancer patients throw away their vitamin C supplements, they need to know rest of the story.

Most of the media dutifully reported the researchers’ claim that the equivalent of 2,000 mg of vitamin C “blunted the effectiveness of the chemotherapy drugs.” But only some of the media included a study author’s incredible statement that “If you take an oral dose even as low as 100 milligrams a day” even “that could be harmful” during chemotherapy.

100 mg “could be harmful”? That’s the amount of vitamin C in a few glasses of orange juice. Something is very wrong here.

Heh. The outrage is palpable. Truly, the heirs of Linus Pauling are most unhappy. Of course, I actually questioned that statement as well as perhaps being a bit over the top when I read the Orthomolecular.org press release. However, I didn’t remember the statement that way; so I went back to news stories about this study. All I could find was this statement by Dr. Mark Heaney, the lead author of the study:

Given that our research was done in experimental model systems and was not a clinical trial, I am reluctant to predict a dose of supplemental vitamin C that could be extrapolated to our work. That said, oral vitamin C supplementation with doses as low as 250 mg over a 1-month period resulted in intracellular vitamin C concentrations in normal white blood cells that were close to those that we studied in white blood cell cancers.

That’s a far cry from what the Orthomolecular.org press release says. Then I found this article on WebMD:

“I think that patients should probably refrain from taking supplemental vitamin C during chemotherapy,” Heaney says.

“If you take an oral dose even as low as 100 milligrams a day you can get concentrations of vitamin C inside your white blood cells that are close to the concentrations that we used experimentally, and that could be harmful,” he says.

The recommended intake of vitamin C for healthy people is 75 milligrams daily for women and 90 milligrams daily for men.

Although a multivitamin with vitamin C “would probably be OK,” taking larger amounts should be avoided while on chemo, Heaney says.

Alright, I’ll concede that Dr. Heaney may have gone a bit too far with that quote, but the science behind his paper was sound. Not that that stops the vitamin C woo-meisters. First, they mention that mice can make their own vitamin C. I’ll get back to that in a minute, but first let’s look at this lovely bit of misdirection:

Secondly, previous research has demonstrated that mice with cancer respond well to high-dose vitamin C therapy. One study found, “With an increase in the amount of ascorbic acid there is a highly significant decrease in the first-order rate constant for appearance of the first spontaneous mammary tumor. . . Striking differences were observed between the 0.076% ascorbic acid and the control groups, which synthesize the vitamin.” (3) Another study concluded that: “A pronounced effect of vitamin C in decreasing the incidence and delaying the onset of malignant lesions was observed with high statistical significance. By 20 weeks, approximately five times as many mice had developed serious lesions in the zero-ascorbate as in the high-ascorbate group.” (4) Interestingly enough, when this research was first publicized, the media discounted these findings saying that mouse studies were not particularly applicable to people.

Why is this misdirection? Easy. The woo-meisters are invoking related but distinct processes. Although they share some molecular mechanisms, tumor initiation is not the same process as tumor progression, and preventing the initiation of tumors does not require the same sort of mechanism of action that killing an established tumor does. Killing an established tumor requires targeting a difference between normal cells and cancer cells in such a way that tumor cells are preferentially killed. The bludgeon of cytotoxic chemotherapy, for example, targets rapidly growing cells and kills them in preference to quiescent or more slowly growing cells. Newer, more finely targeted chemotherapeutics aim their fire at specific molecular changes in tumor cells. Preventing tumor initiation requires a much more gentle approach. One can quibble about details, but the two processes are sufficiently distinct to render the above studies, even if valid, nearly totally irrelevant to a critique of Dr. Heaney’s experiments. Nice try, though, woo-meisters, especially since the effects of vitamin C reported in the literature are maddeningly inconsistent, with some tumors apparently being stimulated and others inhibited.

Now let’s move on to the meat of the woo-meister whine:

However, there is a more subtle, and probably much more important factor they did not consider: all mice make their own vitamin C. Indeed, mice make quite a lot. Adjusted for body weight, mice synthesize the human body weight equivalent of approximately 10,000 milligrams of vitamin C each day. (2) Incredibly, sick mice make even more. Mice given transplanted tumors become sick mice.

[…]

Thirdly, a mouse’s ability to make vitamin C, and a great deal of it, is an overlooked confounding factor that may well render the entire experiment invalid. If the Sloan-Kettering team had tried their experiment on Guinea pigs, their results might have been very different. Guinea pigs are more like human beings in that they cannot make their own vitamin C. As controls for comparison, the researchers also treated “no-added-vitamin C” mouse cancers with chemotherapy. Chemo worked just fine on those mice, by the researchers own admission. And each of those mice was internally synthesizing a body weight equivalent of 10,000 mg/day of vitamin C, even though given none supplementally.

So how come 10,000 mg of vitamin C does not interfere with chemo treatment, and 2,000 mg – or even 100 mg – supposedly does?

Wow. Sounds devastating, doesn’t it? Here’s the deal, though. Dr. Heaney actually measured the intracellular concentration of the major metabolite of ascorbate during his experiments. He didn’t just give the mice vitamin C and not bother to follow how much vitamin C cells were being exposed to. Indeed, it doesn’t matter how much ascorbate mice make; what matters is what the concentration is at basal levels, and that’s low. More amusingly, this particular line of criticism can be turned right back around at the Pauling-ites. Let me make it explicit by rephrasing their question: “So how come 10,000 mg of vitamin C does not prevent the formation of tumors in mice, and 2,000 mg supposedly does?”

Yes, indeed. Two can definitely play that game. In fact, let’s rephrase another question from the press release: “You cannot have it both ways. If a synthesized 10,000 mg of C does not prevent cancer, there can be no real ‘interference’ or ‘blunting’ of cancer formation from a supplemental 2,000 mg. And most certainly not from 100 mg.”

Yes, I like it. The symmetry pleases me greatly.

More amusingly, let’s quote Linus Pauling himself in one of the two studies cited:

Unlike humans, mice produce endogenous ascorbic acid. Nonetheless, mice were chosen as the test animals in this study because high ascorbate intake has been shown to influence the development of certain tumors in mice (2, 3).

In other words, if using mice and similar levels of vitamin C to show that vitamin C prevents tumors is good enough for Linus Pauling, isn’t a bit inconsistent for the Pauling-ites to complain about it when other investigators use mice and it doesn’t show what they want to see? Or is it “heads-I-win-tails-you-lose”?

I think you know the answer to that one.

After utterly lame attacks on this study, the only one of which had some validity to it was the mention that mice studies often don’t translate to humans, what’s left? I think you know the answer to that one, too. Just read the title of the press release. When they can’t criticize this study on the science, attack chemotherapy itself as a treatment for cancer, just like all good cancer quacks do:

The Sloan-Kettering study team seems to have missed the essential point that vitamin C is not just an antioxidant. Inside cancer tumors, it also acts as a prooxidant, killing malignant cells. Comments Dr. Steve Hickey, of Manchester, UK: “Essentially, the paper seems to be rather misguided and shows a lack of understanding of the dual nature of vitamin C in tumors. Chemotherapy has been shown by over 40 years of clinical trials not to work in the majority of tumors, and its use is counterproductive.”

Chemotherapy drugs have come and gone; the five year survival rate for cancer treated with chemo has remained virtually unchanged for decades. Unfortunately, just over 2% of all cancers respond to chemotherapy. Specifically, one scientific review concluded, “The overall contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults was estimated to be 2.3% in Australia and 2.1% in the USA . . . chemotherapy only makes a minor contribution to cancer survival. To justify the continued funding and availability of drugs used in cytotoxic chemotherapy, a rigorous evaluation of the cost-effectiveness and impact on quality of life is urgently required.” (6)

The paper that they cited as the source of the “2%” claim is an infamous study beloved of woo-meisters of all stripes. It turns out that it’s not such an impressive study. Indeed, it appears almost intentionally designed to have left out the very types of cancers for which chemotherapy provides the most benefit, and it uses 5 year survival exclusively, completely neglecting that chemotherapy can prevent late relapses. There were also a lot of inconsistencies and omissions in that leukemias were not included, while leukemia is one type of cancer against which chemotherapy is most efficacious. Indeed, the very technique of lumping all newly diagnosed adult cancers together is guaranteed to obscure benefits of chemotherapy among subgroups by lumping in patients for whom chemotherapy is not even indicated! A letter to the editor listed these problems and several really boneheaded errors and omissions, too:

The authors omitted leukaemias, which they curiously justify in part by citing the fact that it is usually treated by clinical haematologists rather than medical oncologists. They also wrongly state that only intermediate and high-grade non-Hodgkin’s lymphoma of large-B cell type can be cured with chemotherapy, and ignore T-cell lymphomas and the highly curable Burkitt’s lymphoma. They neglect to mention the significant survival benefit achievable with high-dose chemotherapy and autologous stem-cell transplantation to treat newly-diagnosed multiple myeloma [4]. In ovarian cancer, they quote a survival benefit from chemotherapy of 11% at 5 years, based on a single randomised-controlled trial (RCT), in which chemotherapy was given in both arms [5]; however, subsequent trials have reported higher 5-year survival rates. In cancers such as myeloma and ovarian cancer, in which chemotherapy has been used long before our current era of well-designed RCTs, the lack of RCT comparing chemotherapy to best supportive care should not be misconstrued to dismiss or minimise any survival benefit. In head and neck cancer, the authors erroneously claim the benefit from chemotherapy given concomitantly with radiotherapy in a meta-analysis to be 4%, when 8% was in fact reported [6].

The authors do not address the important benefits from chemotherapy to treat advanced cancer. Many patients with cancers such as lung and colon present or relapse with advanced incurable disease. For these conditions, chemotherapy significantly improves median survival rates, and may also improve quality of life by reducing symptoms and complications of cancer.

I love it when woo-meisters cite that article, because it’s so easy to rebut their overhyping of it. I also point out that a lot of the data included in the paper was for tumors and adjuvant chemotherapy, which is where the chemotherapy is used not as the primary treatment (usually the primary treatment is surgery) but as a treatment to decrease the risk of relapse. For such tumors, the contribution of chemotherapy to overall cancer survival is much smaller than that of the surgery.

But, hey, what tactic is left to a woo-meister when his back is against the wall, and the usual distortions are not flying? Yes, there’s only one thing left. That’s right, conspiracy theories and the pharma shill gambit:

Positive endorsements for vitamin C as a cancer fighter are not in the interests of any pharmaceutical company. Scaring the public away from vitamin C might be profitable. It appears that Sloan-Kettering is biased. So are media reports that attack vitamins.

If the Sloan-Kettering study authors’ recommendations to not take 2,000 mg, or even 100 mg, of vitamin C are followed, there will definitely be an increase in the number of people that need chemotherapy.

The stupid, it burns like the intracellular peroxide supposedly produced by large doses of vitamin C. Some things never change.

This attack on Heaney and his study was to be expected. Indeed, I’m surprised it took the Pauling-ites at Orthomolecular.org nearly a week to respond to the article. One thing this attack demonstrates more than anything else is the cult-like thinking of the followers of orthomolecular medicine, which, let me remind you, was championed by Linus Pauling himself. It has all the elements of pseudoscience: citing irrelevant studies; invoking related but mostly irrelevant physiological mechanisms; cherry picking studies; and, most of all, paranoid conspiracy-mongering. That the acolytes of Linus Pauling found this study threatening enough to merit a counterattack tells me that they’re worried. If they weren’t, they would have ignored it.

Personally, I still don’t understand why there remains such an abiding faith in vitamin C. Even the most optimistic studies that purport to show an anticancer effect due to high dose vitamin C report at best a modest ability to kill tumors and then only at ridiculously high doses and concentrations. Any other drug requiring such huge doses for such a modest effect would have been abandoned long ago, particularly if there were any evidence whatsoever from animal studies suggesting that it might interfere with the effectiveness of chemotherapy. That this overarching interest in a drug that by any objective criteria you care to name has such little promise to be made into an effective treatment continues is evidence that the vitamin C is the object of worship of a cult, and Linus Pauling is its prophet.