Wednesday, January 06, 2010

Follow-up to DCA post

You may recall my post on a potential semi-universal cure for cancer.

One of my readers contacted a professional cancer researcher, a friend-of-a-friend, who offered the following input:
  • A quick literature search indicates that there have been promising in vitro studies (using cells grown on plates) which show cancer cells dying after treatment. However,
  • In vivo there has only been one animal study using rats to show a decrease in tumor size (one lab did it with Michelakis as first author on the paper).
  • Keep in mind that nothing is really believable until it can be replicated in other labs.
  • Many other papers indicate that ingestion of DCA in mice caused liver cancer and another showed damage to peripheral nerves.
  • Basically, there are no human or even monkey studies to support the claims of DCA being a safe and effective drug for cancer treatment.
The same researcher then forwarded original versions of two articles:

1. A popular article from Nature magazine, written in March 2007 (almost three years ago, and just a month after the DCA story first came out in the scientific press: Cancer patients opt for unapproved drug


2. An academic (but relatively readable) article by Dr. Michelakis, the researcher who first brought DCA to the attention of cancer researchers: Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. (This article was published in September 2008, but was first received for publication in December 2007.)

The first article takes a generally antagonistic stance toward patients who would ingest "unapproved" drugs:

Jim Tassano, who owns a pest-control and marketing company in Sonora, California, came across DCA when researching alternative cancer therapies to help his dying ballroom-dance instructor. He wanted something that was effective, safe and that he could lay his hands on: DCA fit the bill. He ordered some from chemical supply companies, teamed up with a chemist friend and they worked out a way to synthesize the compound themselves. “I couldn’t walk away from it,” Tassano says. “It could do so much good for so many people.”

Tassano set up two websites. The first of these ( hosts information on DCA and a patient chatroom. On the second ( Tassano is selling his homemade DCA. . . . Many patients taking DCA — acquired from Tassano, chemical companies or other sources — are reporting their progress on
And the problem with this, according to Dr. Michelakis and others?
Although DCA seems safe overall, they point to a clinical trial that was stopped early because those taking the drug developed damage to their peripheral nerves (P. Kaufmann et al. Neurology 66, 324–330; 2006). Without a control group, they point out, it will be impossible to tell whether any improvement in the patients’ condition is caused by the drug. Patients could also be taking DCA that is not of pharmaceutical grade and might contain harmful impurities.

Michelakis says the patients could end up undermining efforts to do a controlled clinical trial if, for example, some develop harmful side effects and the drug earns a bad reputation. “It’s destroying efforts to do this right,” he says. “Any way you look at this, it’s a negative development.”
"Any way you look at it," it's a negative development? From the perspective of the patients who have, otherwise, been given no hope?

The article's author continues:
The battle between dying patients who want immediate access to unapproved drugs and doctors who urge trials and caution is a perennial one. Some patients argue that they cannot wait for trials and should have the right to take unapproved drugs, regardless of the risks.

But there are arguments against this. An estimated 95% of cancer drugs that enter clinical trials do not get approval, many because they are ineffective or unsafe, so patients risk shortening their life or making their last days more uncomfortable.
Okay. But shouldn't it be up to the patients themselves to determine whether they are willing to take the risks? On what grounds should that decision be left to the government or the "powers that be" who get to "approve" drugs for trial?

Oh. And then there's another argument "against" permitting patients to make their own decisions about whether to use "unapproved" drugs:
[I]f patients can access DCA — or other unapproved drugs — there is no incentive for them to enter a clinical trial. So in terms of public health, ethicists argue, more people will be helped if access to unapproved drugs is restricted and proper trials performed.
So, apparently, selflessness is to be mandated by law. You must, by law, sacrifice yourself for the potential of helping others--"one day, maybe, long after you're dead, if we can just get the funding."
Peter Jacobsen, an expert in ethics, health and law at the University of Michigan in Ann Arbor, doubts whether any good can come of the patients’ efforts. They are so desperate to see results, he says, that there is no way they can report unbiased results and no mechanism to ensure the reports are accurate. “I don’t trust the data,” he says. “It’s hard enough to rely on them in clinical trials, let alone this.”
Okay. I'll buy that. I'll buy the need for caution and the need for skepticism. But . . .

Then I read Michelakis' article.

Remember that clinical trial that was "stopped early because those taking the drug developed damage to their peripheral nerves"? Michelakis notes,
[T]he first two randomised control trials of chronic oral therapy with DCA in congenital mitochondrial diseases were reported in 2006. In the first, a blinded placebo-controlled study was performed with oral DCA administered at 25 mg kg-1 day-1 in 30 patients with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (Kaufmann et al, 2006). Most patients enrolled in the DCA arm developed symptomatic peripheral neuropathy, compared with 4 out of 15 in the placebo arm, leading to the termination of the study.
Whoa! Sounds bad!

But he continues:
Seventeen out of 19 patients had at least partial resolution of peripheral neurological symptoms by 9 months after discontinuation of DCA. . . . No other toxicities were reported.
Beyond this,
It is important to note that peripheral neuropathy often complicates MELAS because of primary or secondary effects on peripheral nerves; for example these patients also have diabetes and diabetes-related peripheral neuropathy.
And then,
In contrast [to the negative results of this one study that was terminated], another randomised placebo-controlled double-blinded study failed to show any significant toxicity of DCA, including peripheral neuropathy. In this study only one of 21 children with congenital lactic acidosis treated with DCA orally at 25 mg kg-1 day-1 for 6 months demonstrated mild peripheral neuropathy. Serial nerve conduction studies failed to demonstrate any difference in incidence of neuropathy in the 2 arms (placebo vs DCA). Sleepiness and lethargy, muscular rigidity of the upper extremity and hand tremor were reported in one patient in each group (Stacpoole et al, 2006).
So what is Michelakis' view of the divergent results with respect to neuropathy?
The higher incidence of peripheral neuropathy in adult MELAS patients may represent an intrinsic predisposition to this complication in MELAS or its associated conditions, that is, diabetes mellitus; this toxicity might also be age-dependent. . . . [Moreover, a]s peripheral neuropathy is a frequent complication of taxane, platinum and vinca-alkaloid chemotherapies, the risk for DCA-associated peripheral neuropathy may depend on whether cancer patients have prior or concurrent neurotoxic therapy. . . . [But i]n summary, peripheral neuropathy is a potential side effect of DCA that appears to be largely reversible.
I want to quote one more section from Michelakis' article. Before I do, however, I would like to add some weight to what he said in the section I have just quoted. One of the moderators on, Jay C, comments,
Researchers at the University of Alberta have reported that DCA is relatively non-toxic, since it has already been used as a medicine on adults and children to treat metabolic disease, and for hypertension. It has been known to have some mild side effects in a minority of patients and they include a change in gait [and] some nerve problems, but both of these symptoms appear to be reversible upon cessation of DCA. This is certainly in positive contract to most of the poisons being administered today as "chemo", including IL-2 (requires on[e] week in ICU), Interferon, and DTIC.
So why the apparently special concern over possible complications from DCA? Is it really scientific objectivity at work here? Or, possibly, something else? [Fear of losing power on the part of gatekeepers like the FDA? Fear of lost profits on the part of major pharmaceutical companies? "The preclinical work on DCA (showing effectiveness in a variety of tumours and relatively low toxicity) (Bonnet et al, 2007), its structure (a very small molecule), [and] the low price (it is a generic drug) . . ., provide a strong rationale for rapid clinical translation," Michelakis says early in his article. Oh. I should probably include the last comment that I elided from the immediately preceding quote. One other factor that ought to provide a rationale for rapid clinical translatioin? " . . . and the fact that DCA has already been used in humans for more than 30 years" (presumably without notable safety concerns).]
The concluding paragraph in Michelakis' article adds another note of interest to this reader:
[E]ven if DCA does not prove to be the ‘dawn of a new era’ (Pan and Mak, 2007), initiation and completion of clinical trials with a generic compound will be a task of tremendous symbolic and practical significance. At this point the ‘dogma’ that trials of systemic anticancer therapy cannot happen without industry support, suppresses the potential of many promising drugs that might not be financially attractive for pharmaceutical manufacturers. In that sense, the clinical evaluation of DCA . . . will be . . . [a] paradigm shift.
While I'm at it, I ought to include one last note. A "Note to Proof" appended by the editors of the British Journal of Cancer at the end of Michelakis' article:
Since the acceptance of this review two important papers have confirmed the novel anticancer effects of DCA in prostate and endometrial cancers: Wong JY et al, Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol June 2008; 109(3): 394–402 and Gao et al, Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate 1 August 2008; 68 (11):1223–1231.
[NOTE: If you are reading this article on Facebook, it originally appeared on my personal blog.]
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