Respectful Insolence

Late yesterday afternoon, I was lazily checking my referral logs to see who might be linking to Respectful Insolence™, as most bloggers like to do from time to time (and any blogger who claims otherwise is probably feeding you a line), when I noticed a fairly large number of visits coming from one location, namely here. I was wondering when this would happen, but it looks as though the regulars at The DCA Site have finally noticed some of my writing. Surprisingly, what they say about me is not that bad, although that’s probably because they seem to have found the least–shall we say?–vigorous post that I’ve done on the topic, in which I describe a paper that suggests a mechanism by which DCA might be ineffective against certain brain metastases.

If there was evidence about why self-experimentation is a bad idea for patients to do and unlikely to produce much, if any useful information, this discussion thread provides it. I’ve written about this before; so I won’t belabor previously made points. (No cracks about how that is what I do best, please.)

The discussion thread begins with a report from a man going by the ‘nym of “squareb” with metastatic sarcoma who reports after 24 days on DCA:

The PET/CT preliminary result shows that the primary sarcoma tumor in the thigh is smaller and has less activity on PET. I did have chemotherapy and radiation to the site in January. This may be a delayed effect of the treatment.

The metastatic tumors grossly have not increased in number, but they have increased in size and their activity has increased on PET. The largest tumor that was 6mm two months ago, 14mm last month is now 17 mm in diameter. You can argue that the rate of growth is decreased, but I do not see the dramatic decrease in tumor size as in the rat studies after 3 weeks of DCA.

I do not think DCA does nothing. On the other hand it is not the magic bullet everyone had hoped for. Of course it may not act on all cancers the same way. It will probably be an useful adjunct to use with other chemotherapies or radiation.

You see, that’s the problem. DCA may do something against sarcoma. It may not. We don’t know, and, as I mentioned before, if it doesn’t do anything in squareb’s case, that would not necessarily mean that it was useless against sarcoma. Almost certainly the shrinkage of his primary tumor and its decreased glucose uptake was due primarily to the radiation and chemotherapy. After all, the metastases are still growing. The hard part about writing about this is that I don’t want be too critical of a patient with metastatic cancer or risk destroying any hope he has. On the other hand, the magical thinking going on in this group after squareb’s report that fuels the desire of other cancer patients to seek out DCA outside the context of a clinical trial has to be addressed. For example, someone going by the name of DaveS (DaveScot, I wonder? The answer appears to be yes.) replied:

“The largest tumor that was 6mm two months ago, 14mm last month is now 17mm in diameter.”
diameter = volume (perfect sphere)

6 mm = 0.11cc
14 mm = 1.43cc
17 mm = 2.57cc

The volume of the largest metastatic tumor increased by 13x in the first month. That’s an increase of 1.90x each week. Before starting DCA the tumor got one more week to grow which at that rate would have put it at 2.77cc. The argument might be that growth in the metastatic tumor didn’t just slow down but rather was halted and possibly reduced in volume by 10%. My math should be right but I’m guessing about the exact number of days and it might not be anywhere near a perfect sphere. No additional tumors is certainly good news. This might be very encouraging results.

This is the perfect opportunity to explain to DaveScot (and, hopefully, to everyone else reading) a little bit about terminology used in cancer chemotherapy trials and to take a page out of Tumor Biology 101; first, the cancer trial terminaology. There are generally four possible results that can be observed in a trial of a new chemotherapeutic agent:

  • Complete response: The tumors shrink away to the point that they are no longer detectable by physical examination, imaging studies (MRI, CT scan, etc.), or tumor markers. Obviously, this is the best possible result. Sadly, it is not seen that often in clinical trials.
  • Partial response: This is usually defined to mean that the tumors shrink by more than 50% (or, in the case where tumor volume cannot be measured easily, tumor markers fall by more than 50%) in response to therapy but remain detectable. More recent definitions have at times loosened this criteria to include tumors that shrink by 30% or more.
  • Stable disease: The tumors either shrink by less than 50% or remain the same size. In some trials, this definition may be broadened to include tumors that increase in size during therapy by less than, depending on the trial, 0-25%, although I’ve pesonally always been suspicious of calling any detectable growth above random variation in imaging measurements “stable.”
  • Progressive disease: Tumors increase in size on therapy and/or new metastatic tumors appear.

Depressingly, by any formal definition you want to use, squareb has demonstrated progressive disease on DCA, particularly when coupled with his additional news (see below). Even he seems to realize it, as he states that he was quite surprised that his metastases hadn’t shrunk, given that his alkaline phosphatase levels had fallen. (Once again, this is yet another example of how unreliable most tumor markers are; alkaline phosphatase is quite nonspecific.) He also shows another insight that is notably lacking among others on the DCA Site discussion boards, particularly DaveScot, when he points out that, although he thinks DCA is doing something, he realizes that it isn’t enough by itself. Indeed, he’s discovered one sad fact about cancer that oncologists and surgeons have learned through long and painful experience over many decades (although, I hasten to point out, not as hard as actually having to suffer through cancer themselves): single agent chemotherapy (which is what squareb is trying with DCA as the single agent) usually produces pretty crappy results in solid metastatic tumors. It’s not at all uncommon in the setting of metastatic disease for single agent chemotherapy to result in response rates of 10-20%–or even lower. In addition, the rapid evolution of resistance is quite common when single agents are used, and there’s no reason to expect that DCA will be any different.

This is core of the problem with all this “do-it-yourself” medical experimentation. The people doing it don’t know the very basics of cancer biology, chemotherapy, or how response rates are measured. They do not even understand the basic terminology. Without that background, it’s like trying to design an airplane with no knowledge of aerodynamics and engineering. Most people wouldn’t even think of doing that, but here we have a number of patients (a couple of whom appear to be physicians, even) trying an unproven drug with only a poor understanding of cancer biology. They’ve done a lot of reading, but they appear not to have the basic background knowledge and practical understanding of oncology to put that information into context, truly a case of a little knowledge being a dangerous thing. There’s a reason that chemotherapy trials need to be rigorously designed and standardized, with controls and careful randomization and matching of patients. There’s a reason for all those specialized doctors, nurses, and infrastructure to follow patients on clinical trials to see if they are responding and to monitor them for adverse reactions and complications. Finally, some may point out that it has been observed that all too often there isn’t a good correlation between initial tumor shrinkage by chemotherapy and prolongation of survival. That is indeed true. Some chemotherapeutic regimens that can produce impressive initial tumor shrinkage result in only marginal increases in overall survival. But what is also true is that if tumors continue to grow rapidly through treatment with a chemotherapeutic agent, that agent will almost certainly not produce a prolongation in survival.

Depressingly, one woman named Sandra chimed in with a misguided attempt to claim that maybe DCA is working for squareb after all:

Because we are dealing with cell division, I think logs are required. Based on the formula:
Final tumor volume = starting tumor volume, times 2 to exponent n
“n” being the time required for one cell to divide.
Isolate and take the log of both sides.

Once we know n, we can solve for what the size of the tumor should have been, had it’s growth not been slowed by DCA.

I end up, assuming doubling of cells with no intervention of the immune system and no dying of cells, to get an expected volume of 18.58cc and a diameter of 2.4cm. If I am correct, DCA has been much more effective than initially thought!

Another commenter named Jeff added later:

There are some positives to be taken from this, specifically a decline in the RATE of growth. At this rate of decline, one would expect the tumor size to decrease in size by your next scan. That doesn’t mean it will necessarily turn out like that, of course.

No, no, no.

I’m very sympathetic to patients like sqaureb, but DaveScot, Jeff, and Sandra (and others like nventr and a scientist called Danny–who obviously does not understand basic tumor growth kinetics–in other threads) are making a very basic mistake that would have been obviated by reading a basic oncology textbook, even more so than DaveScot’s ignorant blather about evolution could be obviated by his actually taking the time to understand what evolutionary theory says. (This really is Tumor Biology 101 material we’re talking about here, second lecture, the one after the basics of what cancer is are explained.) They’re all assuming that the doubling time of a tumor remains constant as it grows. It almost always does no such thing. Indeed, doubling times for tumors nearly always tend to become longer as they get larger, a characteristic known as Gompertzian growth, a term that describes tumor growth that is exponential for a time but then levels off and progressively approaches an asymptote as the doubling time progressively increases. Sometimes, due to contraction of the necrotic center, some tumors will even on occasion appear actually to shrink slightly at different times in their history, even if no therapy is given.

Here’s why Gompertzian growth occurs: Tumor doubling time depends on a number of factors, which include primarily: (1) how long it takes on average for a typical tumor cell to divide; (2) the fraction of tumor cells that are actually proliferating; (3) the fraction of tumor cells that are dying (usually by undergoing apoptosis). The first factor is usually fairly constant, but the last two factors can vary considerably as a tumor progresses. When very small, tumors start out basically doubling in size as fast as their metabolism and blood supply allow because a high fraction of the cells are proliferating and few are dying. However, as a tumor gets larger, it tends to outgrow its blood supply, and tumor angiogenesis is not enough to reach the center. When this happens, the center of the tumor tends to die, which is why the tumors we as surgeons resect often have necrotic (dead) centers. Indeed, they not infrequently contain a cheesy, pasty glob of necrotic tumor in the middle. At the very least, the tumor cells in the center tend to become quiescent or dormant (not dividing) because of lack of adequate nutrients and oxygen, leaving a central tumor mass containing dormant and/or necrotic cells, surrounded by a rim of viable proliferating cells that are solely responsible for continued tumor growth and invasion. Indeed, histological sections of a well-established tumor stained for markers of actively dividing cells will frequently show that only anywhere from 0.5% to 20% of the cells are proliferating, with 20% representing a very rapidly proliferating tumor indeed. The end result of this is that, as a tumor grows, the proportion of cells in its total mass that are actively dividing becomes smaller, leading to a longer apparent doubling time for the tumor mass as a whole. More recent kinetic descriptions may have suggested that Gompertzian growth is an oversimplification (what model isn’t in biology?), but, if anything, these newer data suggest that tumor growth kinetics may be even more variable than we had previously thought. Be that as it may, the bottom line is that the tumor doubling time most definitely is not constant for a given tumor and it most definitely does tend to increase as a tumor enlarges, producing a growth curve that usually looks something like this idealized figure, even in the complete absence of any treatment:

i-d34adb28000028c74f4aa195989143bf-Gompertzian_growth.gif

Add to that the uncertainties and inaccuracies in measuring tumors when they are only a few millimeters in diameter, where an error of a millimeter or two can change the apparent volume of the tumor by a large percentage, coupled with Gompertzian tumor growth, and it’s impossible to know where squareb’s tumor was on the curve above when he started DCA, to determine how fast his tumor would have grown without DCA, or to assess whether DCA even slowed its growth down in the least. It’s certainly possible that it has and that more treatment might finally put the brakes on (and for squareb’s sake I hope this is true; this is one time where it would be a wonderful thing for me to be wrong); however, from his anecdote at least, I must, with heavy heart, conclude that it’s highly likely that DCA did not touch his tumor. The same problems hold true for determining response in any one patient. If a tumor shrinks impressively, then one can reasonably conclude that the drug is having an effect; otherwise, because of Gompertzian growth and biological variability in tumors among patients, without doing a randomized trial with experimental groups containing a enough patients to provide adequate statistical power to detect a treatment effect, it’s impossible to tell if a new chemotherapeutic just doesn’t work or whether it actually does slow down tumor growth.

Worse, when combining DCA with chemotherapy, if side effects occur, it can be devilishly difficult to figure out if they’re due to the chemotherapy, the DCA, or an interaction between the two. Once again, that is why clinical trials are needed and why self-experimentation such as this is not only dangerous, but highly unlikely to provide much in the way of useful scientific or clinical information. I can understand why he and Sandra might wish to believe that the decrease in tumor growth was due to DCA rather than Gompertzian growth, but the reality is that DCA probably had no effect, at least for squareb at the dose used. Unless his next scan shows a partial or complete response, we are unlikely to know, although stable disease might be suggestive of some response. Worse yet, in a later comment in the thread, squareb gives some bad news:

On the final reading of the PET/CT there are numerous new nodules. The nodule increase of the largest nodule is from 1.5 to 2.1 cm. Not a good result.

That’s roughly a 2.7-fold increase in the volume of the tumor over one month.

As much as I might sincerely wish it were otherwise and hope that squareb has better results on his next scan, the combination of the rapidly increasing size of the main tumor deposit and the new tumors on PET scan clearly indicate that almost certainly DCA is not working in this patient at this dose. If this were a clinical trial, depending on the specifics of the trial design and the intended treatment time, DCA might be continued for up to a total of two or three months to finish out the protocol, but in the case of rapidly progressive disease while under treatment with the experimental drug strong consideration would probably be made to withdrawing the patient from the trial and trying a different agent or enrolling him on a different trial.

I realize that there are depressingly few options for chemotherapy for metastatic sarcoma, none of them particularly effective, but options do exist. I sincerely hope that squareb abandons his present course, which is clearly not working out, and pursues them. Similarly, I urge everyone self-medicating with DCA to think again about it. squareb’s negative experience does not necessarily mean that the drug doesn’t work, but it does serve as a reminder why unorganized, unsupervised self-experimentation of this sort has the potential to endanger the patients involved, none of whom have any real idea of the risks and the extremely low likelihood of benefit to them, and contributes nothing to medical research. At the end of this, what has been accomplished? squareb and apparently a significant number of other cancer patients have exposed themselves to a real risk, garnered no benefit, and, equally bad, in the process produced no real useful information to guide future use of DCA, as a clinical trial would. Some are likely to be harmed. As much as anyone who doesn’t have metastatic cancer can, I understand the desperation that drove him to do it, but that desperation of cancer patients is what the DCA hype is feeding–and will likely ultimately disappoint. The only information that we’ve gleaned from self-experimentation thus far is that DCA is almost certainly not the miracle cure for cancer that the hype implied.

But, then, we knew that was almost certainly true already before all this reckless and unguided self-experimentation.

ADDENDUM: Walnut has posted his critique on Daily Kos as well.

All Orac posts on DCA:

  1. In which my words will be misinterpreted as “proof” that I am a “pharma shill”
  2. Will donations fund dichloroacetate (DCA) clinical trials?
  3. Too fast to label others as “conspiracy-mongers”?
  4. Dichloroacetate: One more time…
  5. Laying the cluestick on DaveScot over dichloroacetate (DCA) and cancer
  6. A couple of more cluesticks on dichloroacetate (DCA) and cancer
  7. Where to buy dichloroacetate (DCA)? Dichloroacetate suppliers, even?
  8. An uninformative “experiment” on dichloroacetate
  9. Slumming around The DCA Site (TheDCASite.com), appalled at what I’m finding
  10. Slumming around The DCA Site (TheDCASite.com), the finale (for now)
  11. It’s nice to be noticed
  12. The deadly deviousness of the cancer cell, or how dichloroacetate (DCA) might fail
  13. The dichloroacetate (DCA) self-medication phenomenon hits the mainstream media
  14. Dichloroacetate (DCA) and cancer: Magical thinking versus Tumor Biology 101
  15. Checking in with The DCA Site
  16. Dichloroacetate and The DCA Site: A low bar for “success”
  17. Dichloroacetate (DCA): A scientist’s worst nightmare?
  18. Dichloroacetate and The DCA Site: A low bar for “success” (part 2)
  19. “Clinical research” on dichloroacetate by TheDCASite.com: A travesty of science
  20. A family practitioner and epidemiologist are prescribing dichloracetate (DCA) in Canada
  21. An “arrogant medico” makes one last comment on dichloroacetate (DCA)

Posts by fellow ScienceBlogger Abel Pharmboy:

  1. The dichloroacetate (DCA) cancer kerfuffle
  2. Where to buy dichloroacetate…
  3. Local look at dichloroacetate (DCA) hysteria
  4. Edmonton pharmacist asked to stop selling dichloroacetate (DCA)
  5. Four days, four dichloroacetate (DCA) newspaper articles
  6. Perversion of good science
  7. CBC’s ‘The Current’ on dichloroacetate (DCA)

Comments

  1. #1 S. Rivlin
    March 21, 2007

    Losing a brother to cancer (lymphoma) and watching him suffering the pain along with the dashed hopes with every new or renewed treatment he received, my heart is going out for all those who are willing to try DCA. However, most, if not all of them, are trying it while still on their regular anticancer therapy and I assume without their oncologist knowledge. The possibility exists that DCA interferes with the therapeutic action of the regular, prescribed anticancer treatment.

    On the other hand, the real “experts” on the topic, like the one known as DaveS (Dave Springer) should just crawl back into their holes and shutup.

  2. #2 Andre
    March 21, 2007

    I think that this comment is not though.Keep in mind that there are millions of terminal cancer patients who will do everything to live longer.I believe that it should be tried.Only because the results of squareb were disappointing,this does not meant that it wont work in other cancer patients.We should wait for other results of other patients before we can do any conclusive statments

  3. #3 anonimouse
    March 21, 2007

    Andre,

    As Orac explained – outside of the context of a tightly controlled clinical trail, any results garnered from this self-experimentation (even positive ones) will be uninformative. There are too many other factors in play.

  4. #4 squareb
    March 21, 2007

    I agree with some of your comments, and probably would have agreed with more of them a few months back before I was diagnosed with sarcoma. I know a lot about cancer and trained at major cancer hospital. One thing I don’t have that you have is the luxury of time. I cannot wait until clinical trials are over to see if DCA is effective. I knew I was taking a risk. DCA may not work on me. As a physician and scientist, I though the mechanism of action of DCA on cancer in the studies in Cancer Cell article was novel and it made sense biochemically. The results of the animal trials was impressive. Sometimes there was an effect in one week. Even in my desperation, I will not try any promise for a cure that comes out. This one sounded like good science. My conventional options for metastatic sarcoma, as you point out, are not very good. I am glad that I tried DCA. None of my doctors who are treating me or my many physician friends and colleagues thought my decision to try DCA was outlandish. I had their support. If my subsequent treatments don’t work out, I would have agonized on my deathbed wondering if DCA works. I have spared myself that mental anguish. As a physician, I think it is my obligation to help other people. From the beginning, I have said to people, do not take this drug on your own, you need the monitoring of a physician to take this drug. Now that I have shown my result, I hope to spare people the false hope that his some kind of magic bullet that works in few weeks. DCA may help in the treatment of cancer, but it will probably not achieve it without being used in combination with other agents.

  5. #5 Orac
    March 21, 2007

    Although I disagree with your decision and firmly believe that all this unsupervised self-experimentation with DCA has the potential to hurt lots of people and very little potential to help anyone, I can sort of understand why you did it. However, unfortunately, many of the other people on The DCA Site appear to lack even your insight. When people like the the poster boy for a little knowledge being a dangerous thing (DaveScot) tried to spin your story as evidence that DCA is slowing the growth of the tumors down, I felt that it was my duty as a cancer surgeon and researchers to disabuse the denizens of The DCA Site of the notion that DCA was likely to have slowed down the growth of your tumors.

    I assure you, I did not do this to hurt you or remind you of what you are all too aware (although I’m painfully aware that that might have been the end result, no matter how carefully I tried to couch my words), but to prevent them from thinking that your story represents a “success” of DCA and being encouraged to do likewise outside of the context of a properly constituted clinical trial.

  6. #6 squareb
    March 21, 2007

    Honestly, I appreciate your comments. I agree with you that people should not take any drug without supervision. DCA is not a drug without significant side effects as touted in the media. I knew that from the start. I was monitored during my treatment. I am well aware that tumor growth rates are not linear. The doctor who did my scans is analysing the growth rate of several of the metastatic tumors to see if there was any effect of the DCA.

    Going from being a doctor to a patient is hard. The knowledge that you possess becomes a burden sometimes when it comes to coping with disease. I have had a few patients with terrible cancers, who never worried about their disease. They did not really understand their disease, but they just had faith in God and their doctors. Remarkably most of them did well despite overwhelming odds. Ignorance is bliss sometimes.

  7. #7 Abel Pharmboy
    March 21, 2007

    squareb: As another person from a physician/translational science family I wish you all the best. Your point about combining DCA with cytotoxic agents is another area where DCA may indeed have the best chance of proving to be useful for patients like you, but then we open a whole new can of worms with people taking DCA during chemo and not telling their docs and exacerbating the peripheral neuropathy of other agents. This whole situation has given me great angst about others self-medicating who do not have your medical and biochemical experience and knowledge.

    To follow on Orac’s discussion of tumor biology, Gompertzian growth kinetics, and the amazingly small fraction of growing cells in a solid tumor, this fact also explains why cycles of chemotherapy are given (other than to allow the reduced white blood cell number, or neutropenia, to return to normal). As the proliferating cell fraction is killed by chemotherapy much more effectively than the resting cells, the next few layers of resting cells are recruited to proliferate, now rendering them sensitive to the next cycle of chemotherapy. The hope is always that chemo/radiation plus surgery kills/removes the bulk of the tumor before metastasis and/or acquired drug resistance occur.

  8. #8 squareb
    March 22, 2007

    Abel Pharmboy: I agree with you, patients should never hide thier use of DCA from physicians.

    Orac: I do not regret trying DCA. The past three weeks before my PET/CT result were some of the best weeks of my illness. The precurement of DCA was difficult, but since it was successful, in retrospect it was fun. It showed me how many friends and people who just friends of my friends were willing to help me. It showed me the altruism and humanity of people. I felt good during my DCA treatment, because DCA gave me something that is in very short supply when you have a illness such as mine. That thing is hope.

  9. #9 DaveScot
    March 22, 2007

    You failed to note some things and made a mistake about another.

    The mistake: the largest tumor is the primary sarcoma on his thigh which shrunk and showed decreased activity on the PET/CT scan. You completely missed that and wrote about the largest tumor growing. The tumor you wrote about was a metastatic tumor.

    What you failed to note was that there was a lag of one week between the older PET/CT scan and the beginning of DCA treatment. While there may or may not be a Gomptertzian factor it is unreasonable to assume it showed up all of sudden in that specific one week interval. We can safely assume the metastases in question continued growing during that single week at near or about the rate they grew in the previous four weeks. In the previous four week period they grew at a rate of 1.90x per week or 13x for the entire month between scans. In one additional week after that scan we can reasonably presume it grew by a factor of 1.90 or maybe slightly less due to Gompterzian slowing in exponential growth. In the most recent scan the metastatic tumor that had been growing at a rate of 1.90x per week grew only by 1.90x for the entire month. That growth could be and probably is due almost entirely to the single week between the previous scan and the beginning of DCA treatment. I presumed that the law of large numbers applied to tumor growth but that law isn’t like falling off a log – you’re either on it or off it – but rather like going down a gentle slope. Otherwise you’d find tumors that weigh 100 pounds. Oh hold, you DO find benign tumor that are 100 pounds. I guess the Gomptertzian curve applies in all cases except for those where it doesn’t. You also talk about exponential growth of millimeter size tumors. The tumor being analyzed was already centimeter size. The objective observation, while certainly not writ in granite, is that DCA immediately and completely arrested the growth of the metastatic tumors but didn’t begin to reduce them or reduced them by a small fraction. This aligns nicely with the study you cited in another thread where it was found that metastatic brain tumors are half as reliant on abnormal glucose metabolism as primary tumors. The flaw in that analysis is that DCA acts in two ways to fight cancer – by interfering with their normal mode of energy production and also by promoting apoptosis. All in all the results, although still ambiguous, at not at all bad for 24 days on on a chemotherapy threatment that cost $100 and had no apparent adverse side effects that one gets from virtually every other chemotherapeutic drug. The patient is continuing the DCA use and will have another scan in a month although I encouraged him to get another scan in a week to eliminate the ambiguity caused by a lag between the month ago scan and the 3-weeks ago beginning of DCA treatment. At $5000 a pop for the scan and no insurance coverage for more frequent scans I guess that might be a factor. Too bad it’s been two years and counting without even the beginning of a clinical trial where another scan could be done in a heartbeat to clear up any question like this.

    How’s the beginning of a clinical trial for this drug coming along, by the way? It’s been several months since public disclosure of DCA’s efficacy in rats and there’s still not a single sanctioned clinical trial started on it. Surely no patentable drug that has orphan status for other ailments and has been used for decades in clinical trials for other diseases and shows this kind of promise for a new application has to wait this many years for a phase one trial for the new disease. Care to explain that? You can’t cop out with the excuse that no one wants to sign up for a clinical trial when there’s no clinical trial to sign up for. We can’t even test your hypothesis that these unauthorized self-medicators are stopping from requesting participation in clinical trials when there’s no clinical trial for the potential participants to refuse.

    Another point you missed is that the patient discontinued use of DCA a day prior to the scan. Studies of using DCA to treat chronic lactic acidosis show that DCA falls off to ineffective levels in less than 12 hours thus it would be expected that glucose activity in live tumors would still show up nicely after 12 hours of cessation. In fact that’s why the patient stopped using it prior to the scan so it didn’t interfere with detection of live tumors. Even in that case the primary tumor still showed less PET activity.

    Yet another point you glossed over is that his alkaline phosphatase level dropped back to normal. While that’s not sure proof of greatly reduced activity in his disease it still demands an explanation of what caused the drop if not DCA. Feel free to point to any case where sarcoma with typical elevated ALP fell to normal after chemotherapy and it wasn’t at least tentatively interpreted as a positive result of the therapy.

    On a general note I will say that if you drop the hostility and adopt an objective attitude your knowledge of cancer biology could be a boon instead of yet another nattering nabob of negativity about anyone who dares wander off the reservation of FDA-approved courses of treatment.

  10. #10 DaveScot
    March 22, 2007

    I noticed an error in my previous comment. I mentioned a tumor that was centimeters in size. I should have said cubic centimeters in volume.

  11. #11 Nat
    March 22, 2007

    DAVE WROTE: “How’s the beginning of a clinical trial for this drug coming along, by the way? It’s been several months since public disclosure of DCA’s efficacy in rats and there’s still not a single sanctioned clinical trial started on it.”

    Do you think it’s possible to get a clinical trial started in humans in less than a few months, do you? I’m not a cancer researcher myself but in my field even stage 2 trials take a fair amount of time to get going. You need to assemble the right sort of team with access to the right sort of patients you need help. You need money from a public source to run the trial (since the drug companies aren’t going to invest in something they cannot protect via intellectual property laws). You need ethical approval for the study. This takes time and a lot of work before you can randomise the first patient/s.

    DAVE THEN WROTE “a phase one trial for the new disease.”

    Phase one trials are usually in healthy people with no disease. This is the first time in humans bit where everybody hopes it doesn’t hurt normal healthy people. You claim DCA already been thoroughly studied. I’ll accept that for the moment. So now it’s on to phase 2 trials. This is where you try to treat, in a proper randomized controlled trial/s, a small to medium number of patients (i.e. 10-200) to show that treatment has a good chance or not of working. Then comes stage 3 trials. These are the really big trials with hundreds to thousands of patients usually in many different places and sometimes even in different countries are treated also in a randomised controlled trial. Stage 4 is post marketing surveillance (or safety monitoring) where the drug is already being routinely prescribed but is being monitored (i.e. it’s not a randomised trial anymore) to see if it is associated significantly with any rare or long term side-effects (the short term and/or common ones should get picked up in either stage 2 or 3).

    Cancer trials often start in phase 2 anyway given the cytotoxicity of the agents used to treat cancer (you don’t want to put them in healthy people- unethical). This is especially important here in the case of DCA. Given that one of the major reservations is that effective treatment currently exists and will presumably be used in conjunction with DCA and people who understand Pharm better than I do (which isn’t hard) are concerned that there are good reasons to suspect some bad interactions. Horrible sentence- in a nutshell: DCA needs to be tested with the other drugs it will be used with.

    Medical researchers are pragmatic people Dave. We’re trained to be suspicious in an information vaccum when miracle cures are being touted to desparate people. There’s a very pragmatic reason why we need to show that a treatment works before recommending it for general use: we need to know that it works.

    On the emotional front I also need to know that I’m not kidding myself and others with magical thinking before publishing recommendations that are wrong, get used in the real world and up killing people.

    Yours in evidence-based reality.

  12. #12 Abel Pharmboy
    March 22, 2007

    As I noted a few days ago, there are DCA trials ongoing by an Edmonton-based sponsor but not for cancer. Late in my post, I mused:

    Getting back to the sponsorship of clinical trials by CardioMetabolics, Inc., I think we can infer something that supports the contention that DCA’s potential in cancer may be overhyped. A small company will only invest its limited dollars toward indications where it anticipates the highest probability for efficacy. Both Orac and I have noted that perhaps thousands of anticancer compounds show efficacy in animals like DCA, only to crash and burn when they get to human clinical trials. My sense is that the strategists at CMI are aware of this fact and have put their chips on the cardiac surgery market – a Medline search for “dichloroacetate” and “cardiac ischemia” already returns 50 papers, suggesting that far more is known about the utility of DCA in this setting than in cancer and that the probability of clinical success is far greater.

    Still, Michelakis is trying to raise funds to support a trial out of U of Alberta and, in addition to Nat’s points, it’s unlikely that a clinical protocol would be out of IRB review even if submitted at the same time as the Cancer Cell paper.

  13. #13 squareb
    March 23, 2007

    DaveScot: I thank you for your support, but I do not want you to think my experience with DCA is a success story. I really have aggressive disease in my lungs. The nuclear medicine doctor and the radiologist will go over the four monthly PET/CT’s and choose out several nodules to see if there was any effect of the DCA. The primary tumor has decreased in size and activity since the last PET/CT, but this may be a delayed effect of the chemotherapy and radiation I had in January. Anecdotally the pain in my thigh returned the week before I started DCA and disappeared about five days into the treatment. Now three days after stopping DCA the pain has returned. This is anecdotal evidence. You cannot hang your hat on it.

    Metastatic tumors are different in many ways than primary tumors. It may be that DCA works better on primary tumors than metastatic tumors.

    DCA is not a drug without significant side effects. Before I took the drug, I researched many studies on DCA on animals and humans and it does have significant side effects and I was prepared for them and took precautions to minimize them. I still have some tremors from the DCA but the weakness and malaise has mostly resolved. The side effects are one of the reasons I decided to discontinue it.

    I was closely monitored during the time I was taking the DCA. I had weekly blood tests and physician visits. It distresses me that many people are taking DCA on their own without physician supervision. Many of these people are taking DCA in sub-therapeutic doses, so they would not have even a chance of a benefit.

    If you go over what I posted, you will see that “I did not take a dose of DCA on the morning of the test.” I did so that the DCA potentially would have an effect on the PET, since it changes the metabolism of cells, possibly giving a false negative. I did not stop it a day before the test.

    I have not read any anecdotal success stories with DCA, and I have a gut feeling there won’t be any. I think DCA is a useful drug for many things, including cancer. Cancer is not a simple disease. If DCA has any effect, it will probably in combination with other therapies.

    I decided to take DCA at the time, because I was hoping for a cure. The published studies looked good. There was no clinical or anecdotal evidence at the time about DCA’s effect on cancer in humans. Now, a month after I started DCA, looking at other anecdotal stories on Internet sites, my decision would be different. I wish DCA studies on humans came out years ago. It DCA does work, I would have had the assurance that I was following a known protocol with a known success rate.

  14. #14 anonimouse
    March 23, 2007

    Dave,

    Will you please stop arguing with doctors who clearly know much more about cancer and cell biology than you ever will? It. Makes. You. Look. Stupid.

  15. #15 squareb
    March 28, 2007

    This is the results of the four CT scans of the lungs from the initial diagnosis to the present. Most of the nodules that were seen in the initial scan were used. These did not light up on the initial PET/CT, but showed up on subsequent ones. Initially it was thought that these nodules on CT were incidental findings. Nodules were followed through the four CT scans. Chemotherapy Gemzar was given at end of December weekly though the January for five weeks as an adjuvant for the primary tumor. Unfortunately, when you graph out the points the only time the tumor growth is slowed is after the Gemzar treatment. The tumor growth resumed at about the previous pace during the DCA treatment. Tumors are in mm. DCA may work on certain tumors or combination with other drugs, but it obviously did not work on my metastatic sarcoma tumors.

    xxxx Dec 6 Jan18 Feb 12 Mar 19
    Nod1 6.6, 10.9, 11.8, 18.1
    Nod2 —, 5.5, 6.4, 12.4
    Nod3 —, 4.4, 5.7, 9.0
    Nod4 —, 6.2, 8.3, 11.7
    Nod5 3.9, 5.7, 6.1, 10.6
    Nod6 2.1, 5.1, 8.1, Excized
    Nod7 2.5 4.5 5.7 8.0
    Nod8 – 3.4 5.4 10.0

  16. #16 Ron Burk
    April 28, 2007

    “reckless and unguided self-experimentation”

    Whenever a group of people gets blamed for a behavior that shows up over and over again in the same group of people, I think the blamers invariably have a poor grasp of the psychology of the blamees.

    In this case, I think doctors (who, regrettably, all too often imagine themselves to have a fine grasp of patient psychology) rarely have any grasp of the cancer patients’ (sometimes overwhelming) need for self-efficacy. Thus, we get doctors telling cancer patients entering primary treatment that there’s really nothing they can do to help themselves, and that their only choice is to be the passive recipient of brutal treatments. The same doctors are then inexplicably surprised at the steady percentage of patients who are willing to reject standard treatment, even when it offers a clear, or even overwhelming, survival advantage.

    By the time cancer patients are terminal, the doctor’s ability to address self-efficacy needs tend to be even more absent. With their reckless and unguided half-baked theories about who needs “hope”, when, and in what form, some doctors do unforgiveable harm to their patients’ ability to derive the most meaning from what is, barring the rare surprise outcome, the last phase of their life.

    If doctors would spend half the energy they spend berating patient behavior on understanding patient behavior (with the tutelage of professional psychologist, of course — doctors make just awful amateur psychologists), they would be much better at channelling patients’ energies away from the very worst of strategies and maybe even ever-so-slightly increase the number of rare cancer endgame miracles. At the very least, they would drive fewer patients away from productive, standard treatments unnecessarily.

    IMHO :-)

  17. #17 fraxible
    May 12, 2007

    You should check out http://www.thedcasite.com for more recent testimonials. Some of them are highly positive. If you are going to be objective, you must also count the positive reports along with the negative one. By the way, the Supreme Court has declared that dying patients have a right to take such drugs.

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