Several months ago, i wrote quite a few posts about a new anticancer drug that had not yet passed through clinical trials but had demonstrated efficacy against tumors in rat models of cancer. The drug, called dichloroacetate (DCA), is a small molecule that targeted a phenomenon common in cancer cells known as the Warburg effect. Because DCA is a small molecule that is relatively easy to synthesize, the misguided news stories proclaiming it the “cure” for cancer that big pharma wouldn’t fund because it was not patentable spawned a cottage industry of charlatans who used the Internet to sell this drug to desperate patients, who fused magical thinking, confirmation bias, and a poor understanding of the basic principles of cancer and how we determine whether a chemotherapy drug “works” or not into a toxic brew of claims that DCA was producing results when, sadly, it appeared not to be.. This led me to wonder about how a patient’s right to self-determination and to try remedies that were unproven and unlikely to help them should be balanced with society’s need to be able to determine whether a given new drug actually works.
Given that background, I shouldn’t have been surprised to find out that there are now similar movements among patients with deadly diseases, again facilitated by the Internet, to encourage self-experimentation, this time with combinations of existing drugs. I’ve now also found out that this experimentation can be taken to seemingly ludicrous extremes:
Each day, Sam Hutchison swallows 44 pills, most of which weren’t prescribed by his physician. They were chosen by Sam’s father, who devised the treatment cocktail — and tests many of the medicines on himself — in a desperate effort to save his seven-year-old son.
Neil Hutchison, 45, isn’t a doctor. A defense-contractor recruiter, he’s part of a growing underground pushing the edge of medicine to find combinations of anticancer agents to save themselves or loved ones. Many of the medicines Sam takes haven’t been tested in clinical trials for his disease. Some are meant for other illnesses; others are still in animal testing for safety and efficacy. But the fact is that Sam, who suffers a rare and often-deadly cancer of the nerves, is otherwise almost certain to die. Hence Mr. Hutchinson’s decision, as he puts it, to play “lab rat” with his son.
“When your kids have run out of options, you have to think outside the box,” Mr. Hutchison says. “It’s terrifying, but it’s our only hope.”
Mr. Hutchison’s methods are highly unorthodox. Doctors warn that untested combinations of drugs could cause terrible adverse reactions. Science takes time, and some doctors say that trying to shortcut the process is reckless.
It’s only the most hard-hearted who wouldn’t understand a parent’s desire to go to such extreme measures to try to save the life of his child. It’s not hard to understand why Mr. Hutchison might go so far as to turn his child into, as he even admits, a “lab rat.” Physicians even understand that the process by which we determine which new drugs or cocktails of drugs can be cumbersome, and, if a patient or loved one has cancer, seemingly far, far too slow. However, this sort of approach, whether it truly “worked” for Sam or not has the potential to do far more harm than good.
The rationale behind using custom drug cocktails to target specific cancers is similar to the rationale that was used to come up with the drug cocktails that were so successful in treating AIDS in the 1990s, turning a deadly killer into a manageable chronic disease for many of the HIV-positive. Using the same rationale for cancer is highly tempting and now becoming possible. Of course, we’ve always used combination therapies before for cancer and still do. We’ve known for a long time that resistance is quick to evolve in response to therapy with only one drug or sequential therapy with single drugs. It’s thus reasonable to ask what’s different now compared to a decade or two ago. The problem is toxicity. The drug cocktails of the past included chemotherapy drugs that were broad in their targeting. Usually, the only aspect of cancer cells that these drugs targeted was proliferation, which is why they tended to be toxic to rapidly growing normal cells as well to the cancer. The concept then was that the drugs were more toxic to cancer than they were to normal cells. The differences between most drugs in these combinations were that they would target different molecular pathways that led to proliferation. Consequently, when they were combined, the toxicity was frequently extreme and limited dosage and number of drugs. Resistance would also evolve to the combinations because of intermittent dosing schemes necessitated by the serious toxicity the combinations produced.
The difference now is that a new generation of targeted therapies designed to exploit specific molecular differences between tumor cells and normal cells, often molecular differences unique to a specific tumor or group of tumors. One of the very first drugs designed to do this was Herceptin, which targets the Her2/neu oncogene in breast cancer. Other examples of targeted therapies include the drugs Gleevec, Iressa, and Velcade, as well as my favorite area of research, angiogenesis inhibitors. The concept behind drug cocktails is that it is, in theory at least, possible to target all the molecular mechanisms driving tumorigenesis and tumor cell growth, as the drug cocktails for HIV have targeted the various mechanisms by which HIV invades cells and replicates itself in AIDS patients. Given that one of the key advantages of targeted therapies is lower toxicity, it should be possible to use cocktails with more drugs than in the past.
Of course, this concept is not without its problems. For one thing, there’s no reason why multidrug resistance wouldn’t be able to evolve in response to these drug cocktails, just as it can for conventional combination chemotherapeutic agents. More importantly, however, cancer cells are more complicated than HIV. Whereas HIV can be shut down by simultaneously targeting relatively few molecular pathways, the potential mechanisms by which tumor cells can overcome therapies is quite large. Theoretically, at least, for most tumor cells (aside from certain tumors driven primarily by one molecular alteration that can be targeted by, for example, Gleevec) more molecular mechanisms will need to be targeted, and the number of drugs is likely to be larger. Not unexpectedly, the more drugs in the combination, the more potentials for interactions between the drugs and toxcity due to the drugs. Consequently, developing these drug cocktails that will be effective against specific tumors will not be a trivial task. Worse, because most of these cocktails will require drugs from different companies, designing them and negotiating how they will be paid for is a complicated task, a problem discussed in the article. So was the problem of toxicity:
Nick Pavlakis, a 40-year-old Australian oncologist who has helped patients put together combination therapies, says the cocktails don’t work for everyone. Many patients give up because the side effects of the numerous drugs can be intolerable. For some, he says the cocktail seemed to hold the disease at bay only for a time.
None of which would be unexpected.
From the perspective of oncologists wanting to develop these targeted therapies into truly effective anticancer treatments that prolong life and/or increase the cure rate for deadly cancers, perhaps the most vexing problem is that this sort of self-experimentation produces numerous anecdotes that may or may not indicated efficacy of the cocktail tried. (Once again, the plural of “anecdote” is not “data.”) Indeed, this article describes several such anecdotes, a couple of which are somewhat suggestive that a particular cocktail may have worked against a particular cancer. It’s also hard not to notice just how rapidly these “self-experimenters” change their cocktail regimens based on animal studies, cell culture studies, and pilot studies in patients. One also gets the impression that some of the experimentation has little or no rationale, being simply due to the latest hype sweeping its way through the Internet discussion forums and e-mail lists through which self-experimenters trade information and stories. In any case, in most cases this rapid changing of regimens makes it incredibly difficult, if not virtually impossible, for an investigator to figure out which regimen, if any, was effective. Moreover, the potential for harm is large, as changes to regimens are sometimes made in response to tests before the results are even confirmed or followed up adequately:
In October, after the Hutchisons had been shopping for Halloween costumes — Sam chose the “Incredible Hulk” — they learned a radiologist’s report of his latest scan suggested the cancer might have returned in his right leg. The Hutchisons drove home in silence.
Mr. Hutchison berated himself for not adding more cancer-fighting pills to Sam’s daily regimen. He had been digging into research suggesting a mixture of vitamin C and vitamin K3, known as vitamin C:K3, killed cancer cells in a similar way as nifurtimox. He even had ordered boxes of the vitamin mixture and taken it himself, but he had held off giving it to Sam, afraid of adding something new to a drug cocktail that appeared to be effective.
Now, terrified that Sam’s cancer was back, Mr. Hutchison added one vitamin C:K3 capsule a day to Sam’s treatment regimen.
Days later, they got good news. The radiologist, re-reading the scan with the Hutchisons, concluded Sam’s cancer hadn’t returned.
An elated Mr. Hutchison then began questioning his decision to add vitamin C:K3. “I don’t want to over-think this thing,” he said. But if Sam’s cancer wasn’t back, he didn’t want to risk the vitamin mixture. He decided to stop it until he gets the results of a mouse experiment gauging the effects of vitamin C:K3 with nifurtimox, a test funded by a small foundation Mr. Hutchison and three other parents have launched.
This incident also shows just how easy it is for such seemingly rational self-experimenters to start chasing after highly dubious remedies. As I’ve pointed out before, there is no good evidence that vitamin C cures or even does much to treat, cancer. It’s pretty unlikely that combining it with vitamin K3 would make much of a difference.
So what’s wrong with patients self-experimenting with whatever they want to if they have a life-threatening illness? I can understand the desire, and I can understand to some extent the fear and hopelessness that would drive a person to undertake such a research project in which he is the guinea pig. However, in most cases, it is ill-advised and misguided. The odds of success are incredibly long, and the chances of causing significant harm quite high. One could argue that a competent adult, understanding how incredibly low the odds of success are, should have that right. When it comes to children like Sam, however, such experimentation borders on child abuse. It doesn’t matter that Mr. Hutchinson tried out every combination on himself before he gave it to Sam. As pediatricians will tell you, children are not just “little adults.” Moreover, subjecting Sam to such risks without good evidence that it would have a chance to work is highly questionable ethically. That it apparently at least did no harm and may have helped in this case does not change that.
Finally, there is another aspect to this phenomenon. Maybe I’m being sensitive, but the newspaper article seems to portray physicians who would not help Hutchinson or other do-it-yourself cancer treaters design new cocktails or prescribe the drugs as dogmatic, fearful, and unwilling to help, as more concerned about liability and malpractice than about helping the patient. Liability is indeed a concern, but that’s not the main reason why it is unwise and unethical in most cases for a physician to facilitate such experimentation. The real reason comes right down to the cardinal rule of medicine: First do no harm. Coming up with new cocktails on the basis of preclinical studies and questionable rationales may be intellectually satisfying and give the patient hope, but it is far more likely to cause harm than to result in a cure. It is also impossible for a physician provide the necessary information to allow the patient to give truly informed consent when the data upon which these cocktails are based are so new, tentative, and all too often based on little more than cell culture studies or speculation. As frustrating as it can be, there is a reason why randomized clinical trials are so important in determining what does and does not work.