Respectful Insolence

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.

Comments

  1. #1 Marcus Ranum
    December 18, 2007

    A friend of mine’s mom once “cured herself” of breast cancer using some diet based on apricot pits, or something like that. Of course, the cancer later returned and killed her.

    Another important point about these goofy do-it-yourself “cures” is that there’s no real tracking of what “works” and what doesn’t. So nobody can point out that the apricot pit diet “cure” rate is equal to the spontaneous remission rate, or whatever. That might help bias in favor of anecdotal ‘evidence’ about miracle cures. I’ve noticed that whenever I trash accupuncture, someone knows someone whose cousin had a really positive cure, usually of something that would have gotten better on its own.

    (By the way, a side-point: I tried once to compare the ‘miracle’ rate at Lourdes against the spontaneous remission rate and the numbers I got back showed that you’re less likely to have your cancer go away if you go to Lourdes… Maybe this has something to do with the kind of cancers people bring for miracle cures?)

  2. #2 Dangerous Bacon
    December 18, 2007

    Well, home vitamin therapy for cancer is probably safer than glugging down “oleander soup”:

    http://www.cancertutor.com/Cancer02/Oleander.html

  3. #3 Seth Roberts
    December 18, 2007

    “The odds of success are incredibly long.”

    What is this estimate based on? The article mentions Ben Williams, who was successful.

  4. #4 rock science
    December 18, 2007

    I’m a practicing scientist (although not in medicine or pharmacy). I’ve read your comments carefully, I understand your arguments and I realize that there may be a fine line between good intentions and child abuse, however, were my son in a similar situation, I would do the same thing. Given a terminal diagnosis, to do nothing is to do harm.

  5. #5 marion
    December 18, 2007

    The problem with these stories is that they never quote the people who took their own drug cocktails to treat cancer and then died. Because (duh) they’re dead. And there’s no good way to assess who benefits and who doesn’t.

    That having been said, it looks as though the Hutchisons only started with the cocktail approach when their son’s neuroblastoma recurred and they were told that he didn’t have long to live. Correct me if I’m wrong, but I’m assuming that his life expectancy was measured in months at that point, and they weren’t going to be pleasant months. If I had a child in that situation AND if he had just been dropped from a clinical trial because of the prevelence of his cancer, I think I, too, would figure that I had nothing to lose. It looks as though he’s giving the kid a combination of drugs that have been approved in other countries (and not ones lacking real screening processes), substances that have been approved by the FDA, and over-the-counter vitamins and herbs (I take Omega-3 and vitamin C; last I checked, neither was toxic.) From a scientific point of view, Sam’s treatment should be handled differently, but this doesn’t seem to be a situation in which the worst case is that the drugs end Sam’s life sooner and more painfully than the cancer was going to do.

    Again, to be more thorough, there should have been an anecdote about a family who gave their kid something toxic to treat his cancer and ended his life prematurely, but, y’know…I read this site, and I am a strong supporter of the scientific method and evidence-based medicine, but if my child’s cancer recurred and I was told that there were no more new “official” treatments for him, I wouldn’t just take him home to die, either. Maybe the situation wasn’t quite as bad, but the parents basically seemed to have hit the end of the road. If doctors really want to discredit this approach in the public mind, they’re going to have to be willing to talk about the times when it hasn’t worked, rather than just saying that dying people should wait for the outcome of clinical trials. Technically, they may be correct, and everyone in the U.S. should probably read _Arrowsmith_, but there are too many avenues now for people to obtain supplemental treatments for the “follow the rules” approach to carry the day with everyone.

  6. #6 Orac
    December 18, 2007

    The estimate is based on the long history of clinical trials in cancer research, where the vast majority of drugs and treatments fail, as do most trials of combinations.

  7. #7 Orac
    December 18, 2007

    Given a terminal diagnosis, to do nothing is to do harm.

    Straw man argument.

    Palliative therapy is not “doing nothing.” I really hate the apparent attitude that palliation is not worthwhile because it won’t prolong life much or at all.

    That being said, i can understand your rationale, but I could also counter that there is a huge potential to make the child’s remaining months even worse than the cancer itself would make them with only a minimal potential of actually doing something that prolongs the child’s life. Indeed, it is far more likely that such misguided experimentation will make the child’s remaining months more miserable than it is that it will cure him–or even prolong his life appreciably. That the Hutchisons appear to have gotten incredibly lucky does not change that.

  8. #8 marion
    December 18, 2007

    Palliative therapy is not “doing nothing.”

    That may be true, but most parents of cancerous children don’t want to make their lives easier while they die – they want their kids to *live*. In the case of the child in this article, it appears the worst thing that could happen would be that he’d die soon from the therapy – well, he was already supposed to die soon, and would have done so, presumably, if things had progressed as expected. My complaint with the article is that I think someone at some point cherry-picked the most dramatic case and the most reasonable parents – they have a child with a particularly persistent and definitely incurable diseases, they followed conventional medicine until it ran out, they started with a drug approved in other countries, they have founded a foundation that’s conducting clinical trials. That having been said, I think you’re going to find an increasing number of patients and parents for whom palliative care isn’t enough. These aren’t parents of autistic kids who want them to be “perfect” – they’re people who have been told that their kids are going to die soon. The availability of palliative care isn’t going to do much to change their minds.

  9. #9 Calli Arcale
    December 18, 2007

    The hell of it is, though, that choosing to attempt an extensive therapeutic regimen instead of palliative care may result in the patient having a really miserable last few months. I can understand that parents are more willing to risk their child being in agony than risk their child being dead, but I think this is mostly because of the stigma associated with palliative care. People think it’s “giving up”. I recently watched a woman die who had been suffering for a long time before deciding that it was time to let go. One of the greatest mercies they gave her was stopping her regular insulin checks. No finger pricks for the last day of her life. Such a mercy is easy to overlook. Medical interventions all carry a cost. Some are only a little annoying (though taking 44 pills would seem to be quite a bit more than “a little annoying”, especially for a child). Some are mildly painful, like finger pricks. Some are agonizing. If an intervention is too excruciating, and could only prolong life a short time, it may not be worth the price. That’s a hard decision to make, though, especially for another person, and most especially for your child.

  10. #10 Rjaye
    December 18, 2007

    What Calli said in SPADES!!

    I don’t care if a parent thinks that palliative care is not doing enough and that they want their child to live. That is selfish, selfish, selfish. I faced that very same situation, did what I thought would help the person live, and nearly killed her in the most horrible way possible. When I talked with the doctor, he sympathised, and said he saw similar situations every day, and struggled in educating people as to the suffering this attitude and desperation causes. He said it was a rare case where such irrational desperation did not cause worse problems both physically and emotionally for the ill person.

    Wisdom and perspective is hard in such situations, but the road to hell (literally) is paved with good intentions.

    Metta.

  11. #11 Stephen D. Moore
    December 18, 2007

    Are autopsies normally carried out after a person who has cancer dies? Or is it just usually assumed that it was the cancer the killed the person and so noted on the death certificate?

    I ask, because I’m wondering if an autopsy is carried out, and it can be determined that death was the result of drug interactions from a DIY multi-drug regimen, would a person administering such a cocktail to another, (as in the cited example of the Hutchison father to his son) be liable for manslaughter, or some similar crime?

  12. #12 Seth Roberts
    December 18, 2007

    Thanks for explaining where your estimate of “incredibly long” odds of success came from. You say it came from clinical trials, where a “vast majority” of trials failed.

    To say a “vast majority” of trials failed is to say 80 or 90% of trials failed. To say the odds of success are 1-2 in 10 is quite different than saying “the odds of success are incredibly long.” That means something like the odds of success are 1 in 1000 or less. My take is that the evidence you cite doesn’t justify the extreme claim you make; it justifies a claim — an estimate of success — that is much less supportive of your overall argument.

  13. #13 CanadianChick
    December 19, 2007

    What Calli said. Twice.

    If medical science told me that nothing further could be done for my child, I don’t think I’d run the risk of making his remaining months worse with some unadvised mix of drugs and side effects…

    I know, from personal, daily experience, what the side effects of some of those drugs can be on a day-to-day basis when taken at recommended dosages in a carefully monitored regimen – I can’t imagine combining them in a seemingly haphazard manner in the hopes that some combination of 45 pills will miraculously cure my kid.

    I’d rather take him to the zoo or to the park or just hold his hand while he sleeps.

  14. #14 sea creature
    December 19, 2007

    Seth, I think the problem is that the success rate of drug trials and the success rate of a drug/regimen helping are two different things. A regimen may increase the numbers of survivors by 20%, but if only 5% of patients normally survive, then only 1% more wil survive, which is not a big increase. Often these are the numbers that come out of these trials, hence the long odds when you look at the 80-90% failures rates.

  15. #15 Margot Hutchison
    December 19, 2007

    I am Sam’s mother and I have been through three grueling years of treatment with him. I have been there for every needle stick, every 104 degree fever when his counts drop, every vomit, hair loss, severe weight loss, diahreaha, you name it. I have held his hand when he was scared and have had to hold him down for medical procedures. I have signed a consent form for stem cell transplant that stated that I understood that my child might die, would suffer severe hearing loss, and most likely be sterile for the rest of his life. I can tell you from first hand experience that what these children go through for up front therapy is one of the most toxic combinations of drugs given to any cancer – adult or childhood. I have watched child after child die horrible painful deaths from this disease. Neuroblastoma is a disease of the nervous system and death by disease is excruciating, so much so that many of these children cannot get enough morphine to control the pain.

    My father is a physicist. I know about the scientfic method. I understand it’s relevance. However, in a disease where only 600 kids are diagnosed a year, it makes no sense to finish clinical trials that are clearly not working so that they can officially close. It takes too long to accrue kids and doctors are reluctant to open new trials that will compete existing trials. Children are dying every day from this disease and kids are on the same chemo they were being given ten years ago. The pace for pediatric research and trials needs to change.

    The pills that Sam takes are in conjunction with chemo. He has been on protocols since we started this long road. My husband has researched every single aspect of neuroblastoma and cancer in general. If there was an expert, he talked to them, if there was a conference, he went to it or he read all of the abstracts from it. If there was a treatment breakthrough in a cancer with some similarity to neuroblastoma, he spoke to the author of whatever paper was published. He read every book he could get his hands on on cancer and called up the authors. He can state off the top of his head all of the published data on every single neuroblastoma trial. He has created charts on anecdotal evidence of the trials not closed yet. You may or may not believe it but he can hold his own scientifically with any oncologist in the room.

    We are not idiots buying snake oil. Every single thing Sam is taking is backed up by science and the side effects are known because hundreds of people are taking the drugs. He learned how to swallow pills because he had to take them for the upfront treatment. He was on Accutane for six months and kept throwing it up when I tried to mash it up in ice-cream as was suggested so we taught him to swallow pills.

    Nifurtimox has been used to treat Chagas disease in South America for many years.Dr. Sholler was planning a clinical trial, we and some other parents only helped her get it to trial more quickly. She had the data for neuroblastoma. It has been used on children for years and the side effects are well known. We have researched and researched and researched and we agonize over the decision to add things and do so only after carefully weighing data. Sam’s quality of life is very important to me and I don’t take it lightly. I try to make every day fun for all of my kids and appreciate every second with them. Sam’s quality of life has improved dramatically since we cut back to oral chemo and started giving him his current “cocktail.” He went to the basketball draft on Friday night and not a single person in the entire gym would have known he has cancer. He ran up and down the court with all of the other kids and had a huge smile on his face the whole time. I encourage you all to read our web site and learn more about Sam and his brothers and his family who loves him. http://www.teamsam.com I would hope that you would not rejoice if Sam’s cancer comes back in an “I told you so moment.” I cannot predict the future. I can only say that we are doing the best that we can with the information we have at hand. I can also say that as much as we can we make sure Sam lives a regular kid life with his two brothers. He is amazing and our hero.

    Margot Hutchison

  16. #16 Margot Hutchison
    December 19, 2007

    I would only like to add that the majority of the pills Sam is on are non-toxic and don’t have side-effects. We are looking to give these kids less toxicity. The current trials are very toxic.
    Margot

  17. #17 Calli Arcale
    December 19, 2007

    And that is your decision. None of us is in a position to judge your son’s case specifically. We can only express our misgivings based on other cases.

    Getting to Orac’s specialty, my aunt died of breast cancer when I was a little girl. She never realized just how futile her case was; the doctors would pass the job of “bad news bearer” off on interns, who would chicken out and only tell the family. They never told her directly. And so she died believing her case was curable. She died in agony, enduring repeated interventions including chest taps to help treat her pneumonia. (It wasn’t worthwhile; the pneumonia got her anyway.) I don’t know about your son’s case, but I am certain that my aunt’s case was seriously mishandled. She was a clear case of someone who had no hope, and should instead have been allowed to live her final days with some degree of comfort.

    I do hope your son improves. I will keep you and your family in my thoughts and prayers; whether I agree with your course of action or not is irrelevant, because either way you’re going through a horrible time. Take care.

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