Respectful Insolence

I’ve written a lot about a doctor named Stanislaw Burzynski who claims to have much better outcomes in treating deadly brainstem tumors than conventional oncology does. Although the way he claims to do it is through the use of substances he calls “antineoplastons,” which he claimed to have isolate from the urine of patients. Over 35 years after having formed his own clinic and “research institute” to use these compounds to treat cancer and after having had over 60 phase I and phase II clinical trials registered with ClinicalTrials.gov, with none of these completed trials having been published, Burzynski continues on, charging large sums of money in “case management fees” and in general acting as though the same rules that apply to universities, pharmaceutical companies, and biotech companies don’t apply to him. Meanwhile, Burzynski’s propagandist Eric Merola makes yet another conspiracy mongering paean to his hero while melting down on Twitter whenever anyone criticizes him or his hero.

One of the interesting things (to me, at least) about the whole Burzynski saga is not so much his antineoplaston therapy. Basically, Burzynski needs to put up or shut up (not to mention stop treating patients with them) and, whatever happens, admit that antineoplastons are chemotherapy with potential side effects and adverse reactions as bad as some chemotherapies. No, what frequently irks me even more is how Stanislaw Burzynski tries to coopt the concept of “personalized medicine,” except that he calls it “personalized, gene-targeted cancer therapy.” I call it “personalized, gene-targeted therapy for dummies.” Even more irritating, Burzynski is arrogant enough to claim that he is, in essence, the originator of the concept of personalized, gene-targeted medicine, and that big cancer centers like M.D. Anderson, Memorial Sloan-Kettering, and the like are only now following the trail that he blazed.

As much as I do try to get away from Burzynski from time to time, I couldn’t help but think of that smirking, arrogant face pontificating about his genius and bragging about his incompetently administered personalized medicine as I read yesterday’s New York Times article about what real cancer centers are doing to try to develop personalized cancer therapy. Contrast this with Burzynski’s rinky-dink operation:

Electric fans growl like airplanes taking off and banks of green lights wink in a basement at Mount Sinai’s medical school, where a new $3 million supercomputer makes quick work of huge amounts of genetic and other biological information.

Just a couple of miles away, a competitor, Weill Cornell Medical College and NewYork-Presbyterian Hospital/Weill Cornell hospital are building a $650 million research tower. Across the street is a newly completed $550 million tower housing labs for another competitor, Memorial Sloan-Kettering Cancer Center.

Major academic medical centers in New York and around the country are spending and recruiting heavily in what has become an arms race within the war on cancer. The investments are based on the belief that the medical establishment is moving toward the routine sequencing of every patient’s genome in the quest for “precision medicine,” a course for prevention and treatment based on the special, even unique characteristics of the patient’s genes.

Contrast this sort of expenditure and scientific effort to what Stanislaw Burzynski does, which is to use a commercially available test that looks at various immunohistochemical markers and cDNA microarray processing. True, more recently the company offers next-generation sequencing, but does anyone think that Burzynski has the necessary skill to analyze the results. He thinks he does, but an effort to really do personalized medicine requires vast expenditures that Burzynski hasn’t done, has shown no interest in making, and probably can’t do. Worse, the issues in bringing personalized medicine to fruition so that it can be used in every patient and so that it results in improved outcomes are highly complex. They are issues that this article actually discusses surprisingly well for an article designed for the lay press.

Here’s the idea, and it’s an unproven idea: That sequencing every cancer patient’s genome will lead to our identifying better treatments that lead to better outcomes, even cures. Another part of the idea is that sequencing patients’ genomes will allow doctors to predict who will and will not ultimately develop cancer and, if so, which one. Given that it now costs between $5,000 and $10,000 to sequence a complete genome, leaving out the costs of analyzing and interpreting the information. In the search for cures, we’re creating veritable torrents of data, petabytes upon petabytes of sequence and expression data from various next generation sequencing techniques. We still don’t know what to do with this information, nor do we know yet how to interpret the information in a way that guides therapy:

Even optimists warn that medicine is a long way from deriving useful information from routine sequencing, raising questions about the social worth of all this investment at a time of intense fiscal pressure on the health care system.

“What’s the real health benefit?” said Dr. Robert C. Green, a Harvard professor and a medical geneticist at Brigham and Women’s Hospital in Boston. “If you’re a little bit cynical, you say, well, none, it’s foolish.”

Dr. Green is part of a federally sponsored research project that is looking at the economic and medical impact of whole genome sequencing. “One of the most prominent downsides is you start chasing risks for a whole lot of disease you’ll never have, and generate a lot of cost for little benefits,” he said.

Of course, sequencing every genome we can sequence is, in part, in essence screening an asymptomatic population for potentially thousands of conditions that could be found by analyzing gene sequences. Every time anyone’s genome is sequenced, it’s virtually inevitable that mutations or sequence variants associated with diseases will be found. the problem is that, in most cases, the risk of diseases associated with those mutations is not that well characterized; so it becomes problematic what to tell patients. Genetics is not destiny. On the other hand, if the information is there, it’s hard not to treat it as such. We’ve already seen this sort of problem with various direct-to-consumer tests marketed as gene tests, such as 23 and Me.

None of this is to say that personalized therapy, which is now increasingly being called “precision medicine,” much the same way that “complementary and alternative medicine” has become “integrative medicine.” (Yeah, I’m being a bit sarcastic here because the name change to me is pretty pointless.) However, none of this is to say that I don’t think there will be a role for “personalized medicine” or precision medicine or whatever you want to call it. Genomics is here to stay, and I have little doubt that in the relatively near future (as in five to ten years) we’ll be sequencing patient genomes for all manner of diseases and conditions and that many more hospitals than just NCI-designated cancer centers with huge endowments and tons of money to build research institutes costing hundreds of millions of dollars will be sequencing cancer genomes to guide therapy, and it’ll be done right, not the way someone like Stanislaw Burzynski does it.

The problem, as I’ve described before, is that cancer genomes are messed up. Really messed up. I mean, so incredibly messed up that it’s rarely just one set of mutations driving cancer growth. Add to that evolution constantly selecting for more aggressive clones, and cancer might actually be a less fruitful area for personalized medicine than everyone understands. After all, if you find mutations for which there are no targeted therapies, it doesn’t help much, if at all. Even so, contrary to the claims of certain people trying to co-opt personalized therapy, it actually is possible to do clinical trials testing personalized therapy. for instance:

The promise of whole genome sequencing can be seen in trials like one for bladder cancer at Memorial, where the effects of a drug normally used for breast cancer were disappointing in all but one of about 40 patients, whose tumor went away, Dr. Baselga said. Investigators sequenced the patient’s whole genome. “The patient had a mutation in one gene that was right on the same pathway as the therapy,” Dr. Baselga said. “And that explained why this worked.”

As I’ve pointed out before, it will take some rethinking of our clinical trial design paradigms to incorporate new genomic technologies routinely into clinical care. We need to know when it’s useful to sequence a patient’s genome and when it’s not, what we can tell from it, and what we can’t. However, the biggest task is going to be to figure out the clinical significance of hundreds, if not thousands, of mutations and sequence variants. In cancer, the task will be even more difficult because no two cancer genomes are alike, and evolution guarantees that different areas of the tumor can be very different from each other and have different drug sensitivities and resistances.

So what does this mean? Heck if I know right now. I’m actually fairly optimistic, but I also believe that personalized medicine tends to be oversold. There are two things that I think I know right now. First, the NYT article was right to characterize it as a “gold rush,” because that’s what universities are behaving like. The question is whether there is actually any gold at the end of that rush; there might be a lot less than scientists think there are. Finally, I know that the the benefits and scientific advances in personalized therapy will come from real scientists delving into the mysteries of the genome with rigorous science. It won’t come from personalized medicine wannabes like Burzynski.

Comments

  1. #1 Khani
    April 23, 2013

    Orac, I was given to understand by a hospital administrator recently that chemotherapy is given ratings of 1-4 based on severity of side effects and potential complications and the like. (I believe I understood him, but please correct me if I have not.)

    What level would Burzynski’s chemotherapy come in at, do you think? The side-effects do seem quite severe and have already proven lethal in at least one case, so I was curious as to where that would fall on the scale.

    Regardless of whether it’s a 1, 2, 3 or a 4, it most definitely is, as you have said before–chemotherapy.

  2. #2 K
    April 23, 2013

    I think a lot of the confusion around “it’s not chemo” comes from the fact that antineoplastons are HDAC inhibitors (sodium phenylbutyrate, sodium phenylacetate mostly) – they’re not ‘traditional’ cytotoxics like carboplatin, which damage DNA and generally screw up cell division. But they are still very much cancer drugs, and therefore come under the banner of what most people would understand to be “chemotherapy”. Yes, it’s a question of semantics, but ANPS are still (fairly rubbish) cancer drugs, with a huge sodium load and a significant side effect profile. And very lacking in good published evidence of efficacy.

  3. #3 Dangerous Bacon
    April 23, 2013

    “Electric fans growl like airplanes taking off and banks of green lights wink in a basement at Mount Sinai’s medical school, where a new $3 million supercomputer makes quick work of huge amounts of genetic and other biological information.”

    Hah, the Geiers solved the mystery of autism in a world-class lab in their home in the suburbs.

  4. #4 herr doktor bimler
    April 23, 2013

    Electric fans growl like airplanes taking off

    130 decibels sounds a tad noisy for a lab environment but perhaps cell biologists find that it helps them concentrate.

  5. #5 Orac
    April 23, 2013

    And, of course, Burzynski’s solved the problem of “personalized gene-targeted cancer therapy” in his little research institute with no scientists with documented expertise in genomics.

  6. #6 Grant
    April 23, 2013

    “And, of course, Burzynski’s solved the problem of “personalized gene-targeted cancer therapy” in his little research institute with no scientists with documented expertise in genomics.”

    hmm, that does seem just a little unlikely.

  7. #7 Michael Finfer, MD
    April 23, 2013

    Genomics may indeed be the future, but we do not yet know what that future is going to look like. Not only do we not have the widespread infrastructure needed to handle all of the data that will be generated, but there needs to be people to interpret the data once the computers are done with it, and those people do not yet exist.

    I often suggest to people looking for a career in medicine to consider becoming a certified genetic counsellor. It does require a masters degree and an ability to deal with statistics, but I think the future of that field is very promising, and I think that those people will be in short supply within ten years.

  8. #8 Eric Lund
    April 23, 2013

    130 decibels sounds a tad noisy for a lab environment

    That’s not the lab, that’s the cooling system for the computer room. High performance computers generate lots of heat, so the room they’re in has to have a high-performance climate control system. My institute has only a fraction of the computing power these institutes are installing, and the main computer room has to be air conditioned year round–this in a climate where few houses have central air, as long cold winters are routine and even in our brief summers upper 80s is considered a hot day.

  9. #9 Old Rockin' Dave
    April 23, 2013

    It really is appropriate that Burzynski’s antineoplastons were isolated from urine.
    After all, what else is he doing but pissing all over science, medicine, the FDA, the public, and most of all, his patients?

  10. #10 JGC
    April 23, 2013

    Perhaps people having touble understanding antineoplastins are a chemotherapy drug would benefiti from the example of another HDAC inhibitor? If vorinostat represents a chemotherapy drug (and it does) then clearly antineoplastons do as well.

  11. #11 Jenora Feuer
    April 23, 2013

    And, to extend the ‘gold rush’ metaphor…

    There was actually gold discovered a ways from where I used to live some years back. Mining company came in, did an assay, and left again, saying that there wasn’t enough gold in the ground to even pay for hauling over the equipment to start the mine. A lot of the locals were so upset, to the point of asserting the mining company was conspiring against them somehow. (Some people’s brains seem to shut down when seeing the lure of potential riches.)

    On this side… it may turn out that genomics work can’t produce much in the way of cures that we couldn’t get just as well in other ways.

    On the other hand, it may not, and unlike the gold mine where we have lots of experience in mining and can make decisions like this with a high degree of accuracy, a lot of genomics is still in the ‘basic research’ phase, and we can’t know whether or not it’s worth it until after the money is spent. And even if it doesn’t give us lots of cures, it will still give us a lot of useful information we don’t yet have.

  12. #12 Johnny
    127.0.0.1
    April 23, 2013

    It really is appropriate that Burzynski’s antineoplastons were isolated from urine.
    After all, what else is he doing but pissing all over science, medicine, the FDA, the public, and most of all, his patients?

    Must…fight…golden…shower…joke…

  13. #13 herr doktor bimler
    April 23, 2013

    we do not yet know what that future is going to look like

    We are all interested in the future, for that is where you and I are going to spend the rest of our lives

  14. #14 Mike
    April 23, 2013

    @ doktor bimler

    Sounds a lot like my I.T. lab when the 1 rack-unit servers start to spool up. Frightening how loud datacenter class computers can be.

  15. #15 Rich Woods
    April 23, 2013

    @Mike:

    Try a roomful of 4U’s: I reckon it must be chassis size contributing to a damping problem. Anyway, it all gets drowned out by the aircon trying to keep up.

    But back on topic, yes, I think it will be good to start collecting all this data even if we don’t know what the end benefit might specifically be. Of course the trick will be to also record what is known about each patient, then and hopefully into the future, to give the genomic data sufficient relevance.

  16. #16 Old Rockin' Dave
    Under a really big umbrella.
    April 23, 2013

    @Johnny, #12:
    “Your Majesty is like a stream of bat’s piss.”

  17. #17 Old Rockin' Dave
    April 23, 2013

    Just after my last post, I saw that Skeptical Inquirer magazine posted this link on their Facebook page:
    http://www.forbes.com/sites/peterlipson/2013/04/19/a-film-producer-a-cancer-doctor-and-their-critics/

  18. #18 Jay Gordon, MD, FAAP
    April 23, 2013

    What do you think of this line of research? As you’ve mentioned above, the cost of these diagnostics is prohibitive but has certainly plummeted from the cost of the first genome mapping.

    http://www.ncbi.nlm.nih.gov/pubmed?term=pmid%3A%2016709250

  19. #20 Pareidolius
    April 23, 2013

    Herr Doktor, Criswell was wise indeed for here we are in the future spending our lives at a furious rate. That, and had fabulous hair. And I think our scaly overlord might be right about a certain someone ^^^^^^^

  20. #21 flip
    April 24, 2013

    Ah Orac, you missed the most obvious retort ever:

    Just a couple of miles away, a competitor, Weill Cornell Medical College and NewYork-Presbyterian Hospital/Weill Cornell hospital are building a $650 million research tower. Across the street is a newly completed $550 million tower housing labs for another competitor, Memorial Sloan-Kettering Cancer Center.

    Compare this to Burzyinski who has a multi-million dollar home with initialed gates, and a wee little set of offices within a larger factory-style building shared with many other tenants, all the while gouging prices at his own tiny pharmacy, and providing very little out-patient services. Oh, and no need for fancy computers because they don’t generate any data worth recording or using.

    Yes, why spend millions of dollars on new facilities when it can go towards paying your gardener to tend to your mansion?

    In cancer, the task will be even more difficult because no two cancer genomes are alike, and evolution guarantees that different areas of the tumor can be very different from each other and have different drug sensitivities and resistances.

    Can someone explain to me why different areas respond differently? Or is that a really stupid question with an obvious answer?

  21. #22 K
    April 24, 2013

    >Can someone explain to me why different areas respond differently? Or is that a really stupid question with an obvious answer?

    Because even within a single tumour, cancer cells can grow into groups (clones) with a distinct genetic makeup, and some of those clones may have gene faults that make them resistant to a particular drug, while other clones don’t. It’s called tumour evolution. More about it here: http://scienceblog.cancerresearchuk.org/2012/03/07/on-the-origin-of-tumours/

  22. #23 flip
    April 25, 2013

    Thanks K!

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