Hidaeki Tsuda

Dr. Hidaeka Tsuda demonstrates that antineoplastons don't work against colon cancer

oracknows — Tue, 24 Mar 2015 05:00:36 +0000

Dr. Hidaeka Tsuda demonstrates that antineoplastons don't work against colon cancer

Two things have reminded me that it's been a while since I've written about Stanislaw Burzynski, nearly five months, to be precise. First, on Wednesday evening I'll be heading to the city where Burzynski preys on unsuspecting cancer patients, Houston, TX, to attend this year's Society of Surgical Oncology meeting to imbibe the latest research on—of course!—surgical oncology. (If you'll be attending the meeting, look me up. If you're in Houston and want to have a meetup, I might be able to pull it off.) Second, you, my readers, have been telling me there's something I need to blog about. This time around, my usual petulance at being told I must blog about something notwithstanding, I'm inclined to agree (more later). It is, after all, Stanislaw Burzynski.

The last time I wrote about Burzynski was when McKenzie Lowe, an unfortunate child with a particularly deadly form of brain cancer known as diffuse intrinsic pontine glioma (DIPG) whose parents lobbied to allow her to be treated with his antineoplastons when his clinical trials were still on clinical hold. Ultimately, for reasons that still remain inexplicable, the FDA lifted that partial clinical hold, which allowed Burzynski to continue to treat patients already on his clinical trials but prevented him from enrolling any new patients (or, as I put it, the FDA really caved). In any case, there hasn't been much to blog about since the fall, other than noting that the Texas Medical Board (TMB) is trying to do the right thing by going after Burzynski's license again. There have been a lot of motions and counter-motions, but overall the proceedings have thus far been as exciting as watching paint dry. That s why I haven't had much interest in covering their ebb and flow, particularly given that I'm not a lawyer, nor am I familiar with Texas law with respect to regulating physicians other than that it is hopelessly slanted in favor of protecting bad physicians more than the public. I'm waiting for the big one, the actual main hearing. Until then, I'm trying to keep my pessimism from depressing me about the long odds the TMB has trying to finally bring down Burzynski.

One thing that's not going to help Burzynski, contrary to what he apparently thinks, is the recent publication of the results of Hidaeki Tsuda's clinical trial of antineoplastons in colorectal cancer. Before I discuss the trial, let's just take a moment to explain what antineoplastons (ANPs) are. I realize that most regular readers are familiar with Burzynski and his antineoplastons, but given that it's been so long since I've discussed him I figured a brief recap is in order. The detailed story is contained in an article I wrote for Skeptical Inquirer entitled Stanislaw Burzynski: Four Decades of an Unproven Cancer Cure. The CliffsNotes version follows. Basically, back in the early 1970s, a Polish expat physician named Stanislaw Burzynski, while working at Baylor, thought he had discovered peptides in the blood and urine that inhibited cancer which he dubbed antineoplastons. His evidence wasn't the strongest, but it wasn't outside the realm of possibility that he might have been right. Unfortunately, instead of taking the correct, scientific approach, he bolted Baylor and started treating patients with antineoplastons. By the 1990s, to make a very long, complex story short, he ended up setting up a bunch of clinical trials that were shams, that basically let him administer ANPs as he saw fit. Those were the clinical trials that were put on partial clinical hold and later allowed to proceed, a process detailed in posts showing just how many violations the FDA found in its inspections of the Burzynski Clinic.

In any case, one of the biggest knocks on Burzynski is that he hasn't published complete results of his clinical trials, although, as I have pointed out, he's published unconvincing partial results. If there's one thing, however, that Burzynski apologists like to point out, it's a clinical trial in Japan run by Hidaeki Tsuda of antineoplastons in colon cancer. It's a study that featured prominently in Eric Merola's second propaganda movie about Stanislaw Burzynski. Here's the segment from the film:

Dr. Tsuda explains 27 years of ANP research + randomized study now published from BurzynskiMovie on Vimeo.

I discussed Dr. Tsuda's trial in detail on more than one occasion, most notably in my discussion of Eric Merola's second movie about Stanislaw Burzynski. Hilariously, after the movie, Merola complained about how Tsuda's trial was rejected by Lancet Oncology. Of course, I wasn't surprised by this and, in fact, discussed what likely really happened, which, contrary to Merola's claims, was not that Tsuda's work was being "suppressed." (I also couldn't help but mock Merola for whining about what happens to pretty much every scientist, namely having papers rejected.) Interestingly, another revelation that Merola mentioned was that Tsuda hired a ghostwriter to write the actual manuscript.

So where did Tsuda finally publish his work? Oddly enough, he published it in PLoS ONE. I must admit, I wouldn't have predicted that journal, given that it's not exactly known as a journal that publishes cutting edge clinical trials. In fact, although it might be confirmation bias on my part to say so, every clinical trial I recall seeing published in PLoS ONE has been—shall we say?—not particularly good. This one is no exception.

The first thing that struck me about this clinical trial is that it is a negative clinical trial. As much as Tsuda's group tries to paint it as a positive clinical trial, it is not. Let's just put it this way. The trial failed to find any effect of antineoplastons on overall survival (OS) or relapse-free survival. That's a negative trial in any oncologist's book, regardless of other findings.

But let me back up a bit. Basically, Tsuda's trial is a randomized clinical trial involving 65 patients with histologically confirmed metastatic colorectal cancer to the liver. Liver metastases from colorectal cancer are one of the exceptions to the rule that metastatic disease from solid tumors can't be treated for cure in that resecting liver metastases can result in long term survival. In this trial, all of these patients had undergone resection of their metastases or thermal ablation of the metastases and were enrolled between 1998 and 2004 at Kurume University Hospital. These patients were then randomly assigned to receive either 5-FU (a common chemotherapy drug used to treat colorectal cancer) alone by hepatic artery infusion (HAI, control arm) or to receive 5-FU HAI plus systemic ANP therapy, which included intravenous and oral ANPs. One thing that struck me right off the bat is that infusing chemotherapy, particularly only 5-FU, directly into the hepatic artery is already outdated. Given advancements in chemotherapy for colorectal cancer, intravenous chemotherapy using new regimens can do as well or better than infusing 5-FU directly into the hepatic artery (which requires a surgical procedure to insert a catheter attached to a pump and is thus more risky and less desirable than just intravenous chemotherapy).

A curious aspect of this trial is that the investigators specified that this was based on the "number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery." To be honest, I'm still not entirely clear what the authors meant by this. Did the investigators choose which group the patient ended up in based on what was found at surgery? Extrahepatic disease (disease outside of the liver) is a bad sign that portends poor prognosis. What I do understand is that the investigators only enrolled patients with an R0 resection, which basically means that after surgery or thermal ablation of liver metastases from colorectal cancer there was no detectable disease left. Thus, at the beginning of the trial, there was no detectable tumor. That was the point and why relapse-free survival was measured.

There are so many problems with this trial. These problems are now much more apparent now that it's been published. Before, I could only speculate because all I had to go on was Eric Merola's biased and oncologically ignorant discussions of the trial designed to promote it as evidence that Burzynski's ANPs are promising antitumor agents. Now, I can look at the published trial results and state unequivocally that I am completely unimpressed, particularly in light of what I know from Eric Merola's films and other claims made by Burzynski supporters. Yes, this is a randomized clinical trial, but it's also an open label, non-blinded randomized phase II study (more on that later). That means that the investigators knew who was and was not receiving the experimental treatment. It found no difference in overall survival between the two groups and no difference in relapse-free survival (time to relapse) between the two groups. Nothing. Nada. Zilch. Again, that's a negative trial. However, it does report a statistically significant difference in cancer-specific survival, with a median survival time of 67 months for the chemotherapy plus ANP group (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. What does that mean?

At this point, let's review what these various endpoints mean. Overall survival (OS) is fairly straightforward. It just means the time until the patient dies, regardless of cause. It's what I like to call a "hard" endpoint, because it's easy and straightforward. There is no interpretation necessary. A patient is either alive or dead, and investigators know the time from enrollment to the time of death. These are reasons why OS is the "gold standard" for clinical trials testing new cancer drugs. Traditionally, to be approved by the FDA, a cancer drug had to produce a statistically significant improvement in OS. True, as I described discussing the case of Avastin and breast cancer, other measures may be used, but ultimately it comes down to OS. In contrast, relapse-free survival is a measure of the time it takes for cancer to relapse after being seemingly eradicated. In this case, all patients had their cancers eradicated either through surgery to remove their liver metastases or thermal ablation to the point of not having any detectable cancer left; so relapse-free survival in these patients means the time until a detectable cancer relapse is detected, wherever that relapse is.

But what about cancer-specific survival (CSS)? This is a more problematic measure. Basically, according to the SEER Database, it means "probability of surviving cancer in the absence of other causes of death." To get an idea of what CSS means check out Figure 1 in this article comparing and contrasting the various survival measures used for cancer clinical trials. Basically, CSS ignores locoregional recurrence and censors (does not count) non-cancer-related deaths, deaths from other cancer, treatment-related deaths, and patients lost to followup. It also ignores locoregional recurrence (recurrence in the same organ or the regional lymph nodes), new distant metastases, a second primary of the same cancer type, and a second primary of another cancer. In the same article, there is this graph:

Comparison of different survival endpoints in patients treated with curative intention for colorectal cancer, disease stages I-III (n = 332). CSS: cancer specific survival; TTR: time to recurrence; TTF = time to treatment failure; OS: overall survival; RFS: relapse-free survival; DFS: disease-free survival.
Birgisson et al.
BMC Cancer 2011 11:438 doi:10.1186/1471-2407-11-438

Note how CSS produces the highest survival rate, while disease-free and relapse-free survival rates produce the lowest apparent proportion surviving. In any case, CSS has many problems, including:

In this variant, the event is death specifically from the cancer. Deaths from other causes are not "events" and do not cause the curve to decline. Instead, from the time of death forward, a patient who dies from something else is effectively removed from the data. This decreases the number of patients "at risk" from that point forward but does not cause the curve to decline...Disease specific survival has serious problems. Disease Specific Survival ignores deaths which were (or may have been) due to treatment. For a toxic treatment, disease specific survival could be very different from overall survival and it's overall survival that counts in the end. Subtle late effects of treatment can make it hard to even know how toxic the treatment actually was, a problem which doesn't arise when the endpoint is plain survival. Disease specific survival is also known as Cause Specific Survival.

Another problem with CSS is that it is prone to misclassification of cancer-specific deaths, resulting in biased estimates of CSS. In other words, an explicit decision has to be made as to whether a given death observed was due to the cancer. Some deaths will be clearly related to the cancer. In others, the cancer might be a contributory, but not main, factor in the death. This might not be a major problem if the trial were blinded, but the trial was not blinded. The investigators knew who was in each group. It's impossible to rule out subtle biases leading to the classification of more deaths of patients in the control group as being cancer-specific than in the ANP group. Indeed, it's hard not to suspect that this is exactly what happened, given not even the whiff of a hint of a statistically significant difference between the ANP and control groups in other endpoints, such as OS and RFS. It's also hard not to suspect that CSS was not a primary endpoint for the original trial but was added on, post hoc, when it became clear that the differences in OS and RFS were not going to be statistically significantly different. There's no way of knowing, unfortunately, because the trial was not registered from its outset, but rather in 2013. (In fairness, it wasn't required to be when it started; the law requiring clinical trial registration came years later.)

Another interesting aspect of this trial is that I now know who is the ghostwriter for Tsuda's trial. It's Dr. Malcolm Kendrick, author of The Great Cholesterol Con, which is not a promising start. In any case, Kendrick declares publication of the Tsuda paper as a "victory":

I was then contacted by someone, who shall currently remain nameless, who told me that a group of Japanese researchers had done work on antineoplastons as adjuvant (add-one) therapy for patients with liver metastases following colorectal cancer. They did not know how, or where, to publish it. So I agreed to look at it, and try and get it published in a peer-reviewed journal.

They were turned down by Lancet Oncology (no surprise), and a couple of other journals. I suggested PLOS (Public Library of Science), which has a high impact and tends to be a bit more open to non-mainstream articles. So we sat down to write, rewrite, edit, alter and adapt.

To be honest, I have never, ever come across so many objections by the peer reviewers. Stuff that was so trivial, so difficult to answer. Re-write, re-write, re-write. Water down the conclusions. I thought by the end of it, nothing would be left, although the most important points did, just about, survive.

Again, as I discussed above, PLoS ONE isn't really well-equipped to publish clinical trials. Even so, apparently those peer reviewers saw through the hype in the original manuscript immediately (assuming that the first version submitted read anything like what was described by Eric Merola). Good. Interestingly, Adam Jacobs, a UK statistician, comments. Like me, he notes that the primary endpoint (CSS) is an unusual one to use. (It's worth repeating that CSS is almost never—strike that, never—used as an endpoint in trials intended to be used in applications for FDA approval, for the reasons I've discussed above.) He also notes:

Third, and perhaps most importantly (especially in light of my first point), there was no mention of allocation concealment. Do you know if the investigators had access to the randomisation list when recruiting patients? I’m sure I don’t need to explain to you how that would completely invalidate the results of the study if they did.

Yep. Allocation concealment is a procedure that is done in randomized trials to make sure investigators are not aware of what experimental group the patient will be assigned to; i.e., procedures to make sure that neither patients or investigators know what group a given subject will be assigned to. As the World Health Organization (WHO) notes, without allocation concealment, "even properly developed random allocation sequences can be subverted, going on to write:

Within this concealment process, the crucial unbiased nature of randomised controlled trials collides with their most vexing implementation problems. Proper allocation concealment frequently frustrates clinical inclinations, which annoys those who do the trials. Randomised controlled trials are anathema to clinicians. Many involved with trials will be tempted to decipher assignments, which subverts randomisation. For some implementing a trial, deciphering the allocation scheme might frequently become too great an intellectual challenge to resist. Whether their motives indicate innocent or pernicious intents, such tampering undermines the validity of a trial. Indeed, inadequate allocation concealment leads to exaggerated estimates of treatment effect, on average, but with scope for bias in either direction. Trial investigators will be crafty in any potential efforts to decipher the allocation sequence, so trial designers must be just as clever in their design efforts to prevent deciphering.

The methods section of the paper indicates:

Randomization used 50:50 weighting to the two arms and was established by computed macro program in Microsoft Excel 97 (Microsoft Cooperation, Redmond, USA).

Excel? Seriously? Also, how was randomization determined? If anyone had access to the list of assignments beforehand, the process could have been subverted. (See Adam Jacobs' comments in the comment section below.) Not to diss Excel (too much) as it's not that horrible a random number generator, but a spreadsheet is not a particularly secure method of determining subject allocation to different arms of the clinical trial.

Here's an even bigger problem. The trial was also open label, which means it was completely unblinded. The doctors treating the subjects and the researchers analyzing the subjects' scans (not to mention determining whether a death was due to cancer or another cause) potentially knew which group each subject was in. Knowing the treatment group could easily subtly (or not-so-subtly) influence determinations of whether a death was cancer-related or due to another cause. That's why, at the very minimum, the investigators determining if relapse had occurred or if a death is related to the subjects' original cancer or to a different cause. These determinations are not always straightforward. Jacobs is right to emphasize this. Unfortunately, in response to Jacobs' questions, Kendrick's answers were—shall we say?—not at all reassuring. In fact, I think Kendrick was downright evasive. For example, even though he bragged about writing the manuscript, whenever questioned about matters like these, Kendrick told Jacobs to contact the investigators. To characterize such a response as "lame" is being generous. Elsewhere, he says things like:

To be frank, I also know that whatever questions are answered, Adam Jacobs (and many others) will always believe it was fraudulent. Any question answered will be followed by another question, and another question, ad infinitum. At some point, as with any trial, there will be imperfections. I know from past experience, that if I make the slightest error, this is leapt upon and used to discredit everything I have to say, on any matter. I spent a year trying to sort out detailed questions about this study. I really, really, do not want to spend another year doing so. Especially when it will make not the slightest difference. Those who disbelieve this study will continue to do so. No matter what. It is the nature of the thing. Please do not confuse weariness with evasiveness – or any other motivation that you may feel is lurking beneath the surface here. Just because someone demands that I answer questions does not mean that I have to do so.

In retrospect I made a tactical error. I should have just said. If you have detailed questions please contact the lead author, or direct questions through the journal. End of.

Funny, for someone who claims to have spend a year editing the paper and "trying to sort out detailed questions about this study," Kendrick is quick to claim ignorance about a very basic and appropriate question asked by Adam Jacobs. How on earth could he have written the manuscript and not known the answer to this very, very basic question? Is he incompetent? I say yes. And I am not "confusing weariness with evasiveness." I'm correctly calling out evasiveness.

Meanwhile, Eric Merola is making excuses on Facebook in this hilarious post:

Post by Burzynski, The Movie.

Particularly hilarious to me is the claim by Merola that "the Japanese were forced to 'water down' and 'downplay' the significance of the studies in exchange for allowing it to be published by the team of oncology peer-reviewers at PLoS ONE (Public Library of Sciences)." Damn those peer reviewers and their pesky insistence on proper statistics! My only thought was, "Dude, welcome to the real world of science! That's how it's done! Peer reviewers, when they are doing their job, force authors to stick to only conclusions that can be supported by the data. Having published in PLoS ONE myself a couple of times, I also understand the process a bit from the author's perspective. Basically, PLoS ONE is very particular about enforcing the journal's standard that, yes, it will publish pretty much anything (even negative studies) as long as the conclusions are reasonably supported by the science. The moment you go beyond what can be rigorously supported by the evidence in your conclusions and discussion is when the reviewers will stomp on you. I learned that the hard way, and now, apparently, so have Tsuda and Kendrick. Good.

Even more amusing is Merola's further whine:

PLoS ONE might catch some heat for doing the "right thing" here, they reviewed this manuscript and kept watering it down for over a YEAR before accepting it for publication. The Japanese were forced to say things like "Overall survival was not statistically improved" even though the survival was DOUBLE in the Antineoplastons group. They also had to say "Antineoplastons (A10 Injection and AS2-1) might be useful" - instead of "Is useful", etc. Baby steps, we guess.

Seldom have I seen such ignorance. OS was not "doubled" if the difference was not statistically significantly different. That's the definition of "statistically improved," and Tsuda's trial didn't achieve it. As for having the authors say that ANPs "might be useful," I'd actually say that the reviewers were too easy on Tsuda and Kendrick. The very data presented show that ANPs are not useful as an adjuvant therapy for successfully resected colorectal cancer metastases. Again, this is a negative trial. Indeed, the paper notes that three patients died in the ANP arm from other causes: from pneumonia, from myocardial infarction, from an accidental death. These were not counted in CSS, and it wouldn't surprise me in the least if they were the reason why OS was not statistically significantly different between the groups, particularly given that the difference in CSS wasn't impressively different, at least in terms of the p-value (p=0.037).

Poor Mr. Merola. Poor Dr. Kendrick. Poor Dr. Tsuda. They hitched their wagon to Stanislaw Burzynski's ANPs. Now they can't unhitch it. Embarrassment is theirs, as well it should be.

oracknows Tue, 03/24/2015 - 01:00

Categories

Medicine

The "Author Contributions" section states

Wrote the paper: YO HT.

If this is untrue, and the paper was in fact written by Kendrick, I scent a retraction on the way.

Interesting point...

He didn't write it. He did edit.

a sample size of 57 patients was estimated to screen an additive 20% in 5-year CSS in the AN arm with error levels alpha = 20% and beta = 20%

Is this common in the real world?

Adam Jacobs (and many others) will always believe it was fraudulent.

I only read the comment Orac linked to in the original post, but where does Adam Jacobs claim the study was fraudulent? He does say that the CSS metric appears to have been chosen post hoc. But that's "torturing the data until it confesses", not fabricating the data. And even after they have done it (assuming they have done it correctly, a point I am not qualified to evaluate), they get a result that is only statistically significant by a narrow margin. The 95% confidence intervals on survival times overlap, even if only by a few months. And a p-value of 0.037 is still high enough that this apparent positive might well be spurious--there is a reason (beyond the fact that they can) that physicists often insist on 5σ significance, rather than the 2σ level which roughly corresponds to p=0.05, to consider a result positive. So while there may be questionable things about this paper, I don't see any evidence so far to support a fraud charge.

Great analysis, David, but the allocation concealment problem is, I think, even worse than you have made it out to be.

What you have described is the limitations that come from the study not being blinded. They may not matter too much for overall survival (which was negative), but as you rightly point out, they matter a lot for endpoints like CSS and PFS.

But the problem of allocation concealment is subtly different. That's about whether, when faced with a patient whom the investigators might or might not choose to enrol in the trial, they can know in advance which treatment group the patient would be in if that patient is indeed recruited.

And that is in many ways a more serious problem.

Imagine if you are faced with a patient who is very ill and you suspect has a particularly poor prognosis. It's not beyond the bounds of possibility that you would be more likely to make the decision to enrol that patient if you knew that the next treatment on the randomisation list was the control group than if it was the ANP group.

So allocation concealment is not the same thing as blinding. You will always have good allocation concealment in a properly double-blinded study, but you will only have good allocation concealment in an open-label study if you take proper precautions to make sure the investigators don't know what the randomisation list looks like until each patient has been definitively recruited. There's nothing here that tells us that allocation concealment was achieved.

So in other words, if there was no allocation concealment, then not only was the study not blinded, it wasn't even properly randomised.

Actually, this is an open label study. It's not even blinded. Which is OK for a hard endpoint like OS, but definitely not OK for RFS and CSS, both of which are judgment calls, CSS more than RFS.

If methodological problems with a study are so big that even a brorderline scientifically illiterate person, such as me, could point to them (well, some of them at least) it means the study is pretty bad.

I decided to alter the discussion about allocation assignment somewhat because Adam is correct that I came too close to conflating proper blinding and allocation assignment. Also, the study is unblinded; so discussing blinding in such detail is unnecessary.

A young rapscallion has a response to his letter in Nature.
The role of academic health centres to inform evidence-based integrative oncology practice REPLY
http://www.nature.com/nrc/journal/v15/n4/full/nrc3822-c4.html

The role of academic health centres to inform evidence-based integrative oncology practice CORRESPONDENCE Published online 24 March 2015
http://www.nature.com/nrc/journal/v15/n4/full/nrc3822-c3.html

Forgive me if I am late to the discussion, my wife always compliments me for my lateness and accuracy.

After reading the Nature opinion letters linked in comment #10 (thank you Dr. Johnson), I do have one minor quibble with one aspect of Dr. Gorski's reply. He states: "Combine equivocal (at best) clinical trial evidence regarding acupuncture with its extreme biological implausibility, and the most parsimonious explanation for the reported effects of acupuncture remains that it is a theatrical placebo, regardless of reported functional MRI findings."

I think the functional MRI findings are significant and should not be discarded as irrelevant. Given that acupuncture has not been shown to work at greater levels than placebo, I put forward as a hypothesis that the acupuncture functional MRI results should be examined as mechanism of action for the *placebo effect* in pain relief. If people are fooling themselves into thinking they have less pain through their imagiantions, then a similar functional MRI should result from other similarly ineffective 'alternative medicine' scams causing pain relief placebo effects. The sCAMsters might have hit upon some real science, just not in a way that supports their delusions.

I think the functional MRI findings are significant and should not be discarded as irrelevant. Given that acupuncture has not been shown to work at greater levels than placebo, I put forward as a hypothesis that the acupuncture functional MRI results should be examined as mechanism of action for the *placebo effect* in pain relief. If people are fooling themselves into thinking they have less pain through their active imaginations, then a similar functional MRI should result from other ineffective 'alternative medicine' scams causing pain relief placebo effects. The sCAMsters might have hit upon some real science, just not in a way that supports their delusions.

@Dr. Johnson and JerryA: Your comments are way off-topic for this post. (Particularly you, JerryA, posting three identical copies of the same post so that I had to delete two of them.) Stop it.

My apologies for both the off-topic comment and multiple identical comments posted. The multiple posts were not intentional.

I probably wouldn't have been so annoyed if not for all the duplicates.

Someone has mentioned a phase 3 trial of antineoplastons. Should be interesting.

"This one is no exception. PLoS ONE"

I see what you did there : )

I was initially really skeptical about PLoS One, but I have to say it has become much more prestigious than I ever thought it would. A mixed bag for sure, but some good papers there.

If AS2.1 and A10 are, as claimed, Histone De-acetylase Inhibitors (HDACi), it would unsurprising to see at least some improvement in recurrence free survival. Just like thousands of other drugs, it's not enough to be effective... you have to be more effective and well-tolerated than current therapeutic options. How, for example, does AS2.1 compare to Vorinostat? Anyone know?

Gosh, it's amazing that this is the first real trial in so long, considering how many trials Burzynski has opened and chosen never to conclude or publish. It's almost as though he had a business model that allowed him to exploit the research trial system to make massive profits. Would that make him the most beloved millionaire Pharma CEO in history?

Japanese researchers had done work on antineoplastons as adjuvant (add-one) therapy for patients with liver metastases following colorectal cancer. They did not know how, or where, to publish it. So I agreed to look at it, and try and get it published in a peer-reviewed journal.

I don’t do clinical research, so I’m asking very honestly: is this something that actually happens? Researchers design and execute a trial in human subjects, THEN try to figure out how to navigate the publication process?

Perhaps the group just didn’t know how to force a weak study into publication?

Excellent comments, except for your criticism of the Texas Medical Board. If you do your research, you will find that they are very aggressive at going after even minor infractions, to the point where they are heavily criticized for being draconian in the handling of stuff like not documenting your CME well enough. Unfortunately, once it goes into the legal system, the lawyers can drag stuff like this out forever, and evidently Burzynski has high dollar lawyers.

The example of Stanislaw Burzynski, and two other big examples I'm aware of, would argue otherwise, not to mention the article I cited about how much the law in Texas is stacked against the TMB in terms of stripping bad doctors of their medical licenses.

This was a nice touch:

Antineoplastons, A10-I and AS2–1, provided by Dr SR Burzynski (the patent holder of antineoplaston A10 and AS2–1, Burzynski Institute, Houston, TX, USA)

I mean, they're expired, but he owns them, dammit!

And a p-value of 0.037 is still high enough that this apparent positive might well be spurious

I'm entirely unqualified to do this, but naively applying Colquoun's approach to false-discovery rates, I'm getting FDR = 20% for P(real) = 0.5 and FDR = 69% for P(real) = 0.1.

Everything about this paper/trial is bizarre.
Dr. Malcolm Kendrick says that the Japanese researchers didn't know "how or where" to publish the results of their trial. Really? have they never read a paper before? I just find it unlikely that a whole team of researchers who are capable of putting together a (not good) clinical trial have *no idea* of what journals are out there where they might publish their results.

I use Excel for randomization for little lab experiments, but for a clinical trial? Uh, no. Don't you at least have STATA?

I can understand not wanting to have OS as your only metric, if only because it can take a really long time to collect enough data, and that can be frustrating/problematic for trials with limited funds. But you've got to pick something better than CSS, which looks like "how to make your data look the best!"

It's really weird.

@ CTGeneGuy

Researchers design and execute a trial in human subjects, THEN try to figure out how to navigate the publication process?

I don't do clinical research, so my input could be of limited value, but it did happen to a few of the research projects I was involved with to first be completed, and then we started talking about which journal we could try to submit the results to.

That being said, the discussions were on the lines of "we did manage to publish in journal X before, let's do it again" or "this article from the renowned Dr Smith has been instrumental in our project, let's try to publish in the same journal".
Or simply "Journal Y is still in the upper tier in our field?" " Yeah" "Do you think our work is good enough?" "Um, yeah" "Let's go for it".

I have to admit, the bit about a scientific team not having a clue where to publish and needing an outsider's advice sounds amateurish, to say the least.

They were turned down by Lancet Oncology (no surprise), and a couple of other journals.

I think this, plus a bit of language barrier, is why Dr. Tsuda's group "did not know how, or where, to publish it." There is no shame in aiming high and failing in your first attempt to publish a paper. But according to Dr. Kendrick, this paper was already a three-time loser by the time he was brought in. That tells me there was something seriously wrong with this paper--I've had papers rejected before for trivial reasons and then accepted at another journal, but when this happens multiple times, it's more likely that the referees agree that this paper isn't up to snuff--and not just with English usage, as there are professionals out there who will edit papers to bring the English up to snuff. Kendrick basically admits as much when he says that he hadn't seen so much pushback from the referees at PLoS ONE. I think it's more that Tsuda got lucky with referee roulette at PLoS ONE, in that he got referees who were willing to recommend major changes rather than outright rejection. (This is one reason I occasionally see papers where my reaction is, "How the #&*@ did this get past the referees?") So Tsuda and his colleagues complied with the referee's suggestions, to the best of their ability, and the editor accepted the paper.

I know a little about pseudo- and true- random number generation, albeit when applied to ciper use. I truly, truly would not advise anyone to use Excel to give them a serious random component. Even the somewhat farcical PuttyGen 'squiggle the mouse' method is an improvement, a considerable improvement.

I am genuinely astonished they would even think about using Excel for this. Surely there were funds to build a hardware true random number generator? You can solder a pretty good one together from bits in the Maplins catalogue for less than £30... Or even the RS catalogue if you insist! Surely they had access to at least one electronics engineering undergraduate??? I mean, most of us would have done it just for the attention!

Jesus H God-dancing Christ...!!! An Excel visual basic for applications macro... That's a good one.

I am genuinely astonished they would even think about using Excel for this. Surely there were funds to build a hardware true random number generator?

I'm missing the part where the quality of the Excel PNG per se isn't a red herring. The description provided, which is opaque to me, reads in full,

"Eligible patients were randomly assigned to receive systemic antineoplastons plus 5-FU HAI (AN arm) or 5-FU HAI alone (control arm) by a minimization method using number of metastases (1–3 vs ≥4) and presence or absence of prior extra-hepatic metastases which were removed completely (R0 resection) at the time of surgery. Randomization used 50:50 weighting to the two arms and was established by computed macro program in Microsoft Excel 97 (Microsoft Cooperation, Redmond, USA)."

They obviously needed roughly equal numbers in each group, which rules out simple coin-tossing for N = 57, and they needed to account for two other variables.

If someone familiar with actual study design could point me in the direction of a clue, it would be much appreciated, but naively, it seems as though the details of the algorithm would be the point of interest.

Its just... Hugely amateur.

I suppose they didn't absolutely NEED truly random numbers. Nonetheless it doesn't in my opinion reflect well on the professionalism of the rest of the project. Moreover given how flawed, or just outright absent the blinding was then any true entropy during their selection process becomes all the more valuable. Instead they used a visual basic routine and a number-sequence... Horrible.

My vague understanding of "minimization method" is: the pool of patients was divided into 4 sub-groups then each subgroup was randomly divided 50-50? Perhaps those subgroups were thus small enough that the crappy choice of randomizer was unlikely to have much impact... particularly given the other HUGE GAPING FLAWS? Seriously, I have never designed a study, never really learned how to, but even I can see how they completely opened themselves up to reporting bias.

(subgroups being: a. 1-3 no r0, b. 4+ no r0, c. 1-3 yes r0, d. 4+ yes r0, each needing to be divided evenly, do I have that right?)

Instead they used a visual basic routine and a number-sequence… Horrible.

For one-off purposes, there's no shortage of transcriptions of numbers-stations transmissions that aren't Cuban. Then again... Venona!!1!

But seriously, the number of substrings with equal numbers of 0's and 1's for n total digits is the number of pair swaps necessary to count from all 0's to all 1's. The number of strings obviously grows as 2ⁿ, but this has a certain O(n lg n) feel to it. (I'm too lazy to find the correct answer.)

One could probably just enumerate them all and pick one out a hat.

^ Or I could not be an idiot and observe that it's n choose n/2.

^^ And the whole digit-swaps thing is complete horsesh*t, sorry.

@CTGeneGuy:

"I don’t do clinical research, so I’m asking very honestly: is this something that actually happens? Researchers design and execute a trial in human subjects, THEN try to figure out how to navigate the publication process?"

Yes, it happens far more often than you think. And I speak as someone who spent 15 years running a company providing clinical research consultancy services, one of which was helping researchers figure out how to publish their results.

There were probably 2 things that made it hard for these researchers to get published:

1. The language barrier

2. The appallingly bad design of the study, which would have meant that any respectable journal would have not felt it worth publishing

@Narad:

"I’m missing the part where the quality of the Excel PNG per se isn’t a red herring."

Yes, I think you're right about that. Using Excel in a clinical trial certainly smacks of amateurism (I have worked on many randomised trials over the years, and I have never once come across a randomisation list that was generated with Excel), but actually, as long as you do everything else properly, there's no real reason why you shouldn't use it.

The problem here is they didn't do everything else properly. Really, really, far from it.

For those concerned about the fact that Excel only generates pseudorandom numbers and not true random numbers, that's true, but that's also true of pretty much all the tools that the best researchers use for random number generation. If you used Stata or SAS for your randomisation list, you would still get pseudorandom numbers. Maybe Stata and SAS have better pseudorandom number generation algorithms than Excel: I don't know. But I don't think that's really the point.

The point is this. If you are the investigator in the study, and a patient walks through the door of your clinic, do you know which treatment that patient would get if you enrolled that patient into the study?

That's the only question that matters.

Now, let's suppose the investigator knew which treatment the previous patients had received. In this case, that's almost certainly true, because this is a single-centre study. In a multicentre study, you wouldn't necessarily know what patients in other hospitals had had, but if all patients are treated in the same place, you do.

The randomisation algorithm only has to be unpredictable enough that the investigator couldn't predict what the next treatment would be from knowing the previous ones. I'm pretty sure Excel would be good enough for that.

But, and here is the real fatal flaw in this study, all this assumes that the entire randomisation list isn't sitting on the investigator's desk right in front of him at the time. If the whole list is in front of his nose, then of course he knows what treatment the next patient will receive. There is nothing in the paper to state the the randomisation list was concealed, and given the amateurish way it was done (this is probably the most important thing the use of Excel tells us), I strongly suspect that entire randomisation list was known to the investigators in advance.

Now, then you're talking really weapons-grade design flaws.

If the investigator knows which treatment the next patient will receive, then the potential for bias becomes huge. Suppose the next treatment on the list is ANP. The patient who walks through your door is very seriously ill, and you don't expect that patient to last all that long. You don't really want patients like that in the ANP group, as it might make ANP look bad. So you tell that patient to come back next week and maybe you'll talk about the trial then. In the meantime, a much healthier patient walks in, who gets cheerfully enrolled in the study, and assigned completely not at random to the ANP group. The sick patient comes back next week, by which time the next treatment on the list is the control group, and then gets recruited into the study.

Repeat that 65 times and you could end up with seriously unbalanced treatment groups.

And yet they still couldn't show a significant advantage of ANP!

There's a further problem with the randomisation. If you look at the links to supplementary material, you can download the protocol. Now, one rather fishy thing about the protocol is that protocols are supposed to be written before you start the study. The protocol here includes the information that patients were recruited between April 1998 and August 2004. Pretty fishy given that the protocol is dated February 2003, don't you think? OK, protocols sometimes get amended after the trial starts, and sometimes for perfectly legitimate reasons, but there really ought to be a transparent description of what changed and why. We are told nothing about that.

But that aside (though we really shouldn't put it aside, because it's extremely serious), the description of the randomisation method in the protocol is completely different to what is described in the paper.

The protocol says that the treatment assignment was done using minimisation, not randomisation. For such a huge discrepancy to exist between the protocol and the paper is pretty serious stuff.

Now, minimisation is a perfectly reasonable alternative to randomisation in some circumstances. It all comes down to whether the investigator can know the next treatment before a patient is enrolled. But because minimisation has an element of predictability, it is never suitable for single centre studies. It can only be sufficiently unpredictable if you have a multicentre study where you don't know what treatment patients in other centres got.

So really, one way or another, there is something extremely worrying about the randomisation method here. I would go so far as to say that this wasn't really a randomised trial at all.

But seriously, the number of substrings with equal numbers of 0’s and 1’s...

...which is why many modern trials use permuted block randomization within each stratum.

Repeat that 65 times and you could end up with seriously unbalanced treatment groups.

And yet they still couldn’t show a significant advantage of ANP!

You know, now that you mention it, if this did happen, then it suggests that the ANP patients probably did worse enough to eliminate the expected difference in outcomes between the ANP+HA chemo and HA chemo alone groups. If your educated speculation is true, it really makes one wonder if ANP actually harmed patients.

@Orac - that is an interesting supposition, given the serious side-effects that come with using ANP....as has been evidenced by the public patient experiences shown over at TOBPG.

One thing I like to point out is this. Our speculations are based on what is in the paper and our knowledge of clinical trials and, at least to me, do not constitute a charge of scientific fraud. They do, if true, however, constitute a charge of scientific incompetence.

Ignorant question by a non-scientist, but wouldn't the definition of "cancer-specific survival" exclude deaths caused by ANPs themselves? We know they killed at least one patient, and if sicker patients in the ANP branch were more likely to die of the ANPs, that would raise CSS without lowering OS (since equally sick patients in the control branch would also die, but of the cancer).

Correct. That is one of the problems with CSS. It excludes deaths due to treatment toxicity.

"We know they killed at least one patient" -- not in this trial of course.

You know what I find interesting, how well what I was taught about clinical trial design comes out in studies like this and TACT. If you have a poorly done clinical trial, with a lot of what I would term "protocol squishiness" (note this is different from an a priori pragmatic design), what would one expect to see? One could expect a marginally significant main result (very likely spurious) and a more pronounced result in subgroup or secondary analyses (likely due to protocol variations which are more impactful in such a group).

What do we see here? and in TACT? That's right, exactly this phenomenon.

…which is why many modern trials use permuted block randomization within each stratum.

Yes, I had seen that before I got distracted by finding substrings generally [n choose k turns out to be Θ(nᵏ), but it's not necessary to enumerate them all to construct a single entry, which is just any ordered sequence of k elements of {1, 2, . . . , n}].

^ For k = n/2, that is.

Let's see if I've got this straight ...

If I feed sugar pills to the control group and sugar pills to the homeopathy group, and then shoot half the homeopathy group dead, I've practically ensured that the homeopathy group has better CSS than the controls?

Wow Adam Jacobs, that is significant if the protocol was written after treatment started and specified a different randomization than was stated in the paper. I agree as well, if they were up to shenanigans and they still couldn't improve survival at all then ANPs must be worse than we thought. Which is hard to believe. The CSS analysis seems ad hoc, added at the end so that they had something to say was positive to their supporters. What is even sadder is that the supporters will believe it.

If I feed sugar pills to the control group and sugar pills to the homeopathy group, and then shoot half the homeopathy group dead, I’ve practically ensured that the homeopathy group has better CSS than the controls?

It would seem so. You could accomplish the same thing by feeding the homeopathy group Conium Maculatum .001X.

Orac (#37):

"If your educated speculation is true, it really makes one wonder if ANP actually harmed patients."

Indeed. Though of course it is just speculation. There is certainly a potential for extremely biased treatment assignment. If the investigators acted dishonestly, then treatment assignment would have been very biased, and if so, it's quite likely that ANP was actively harmful. However, we don't know that the investigators acted dishonestly. Having said that, even if they acted honestly, subconscious biases might have influenced the treatment assignment. But if they were honest and good at controlling their subconscious urges, then it could have been a fair allocation of treatment (though I note from table 1 of the paper that control patients had had longer since original surgery, suggesting they were further along in the course of their disease).

And even if it was fair, of course, there's still the inescapable fact that there was no significant effect on overall survival.

The operation was a success!!!!...........Unfortunately,.. the patient died.

Andreas Johansson@46:

If I feed sugar pills to the control group and sugar pills to the homeopathy group, and then shoot half the homeopathy group dead, I’ve practically ensured that the homeopathy group has better CSS than the controls?

You should apply for a job at NCCAM, mate. They could really use the help getting positive results for a change.

Hi, nice post, thanks!

Just one point to make though. You say 'The very data presented show that ANPs are not useful as an adjuvant therapy for successfully resected colorectal cancer metastases'.

Not wanting in any way to lend support a process that is outside of proper scientific medicine (you know who etc. etc.), but, but:

You cannot use failure to reject the null to support the null hypothesis. You failed to reject the null is all. No more. At least in the frequentist framework. This isn't evidence they 'antineoplastons' don't work. Even if it were a proper trial of a nice big size, and it were negative, you still logically can't support the null. Reason being that there are essentially infinite other models you could have also failed to reject. Sad and frustrating, but that is how, in some sense, hypothesis testing is a bit of a let down.

Ugh. Pedantry.

I know all that. On this this blog (and elsewhere) I emphasize science-based medicine, which is Bayesian, not frequentist. Given what we know about the biology of ANPs, previous clinical trials, and Burzynski's history, it is entirely appropriate to simplify the whole frequentist discussion, turn it into a more Bayesian angle (not to mention aim it at lay people) and say that Tsuda's study is evidence that ANPs are not useful in this context.

There's also sarcasm. Did you not detect the sarcasm in the title and in that statement to which you object on frequentist grounds? It's there to tweak Burzynski and his propagandists.

So should a professionals for ex. oncologists then completely dismiss current research regarding ANPs as possible treatment of specific cancers, or should they build on this research until a more modern and scientific verification has been introduced?
15009212

JJ: No, they should not "dismiss current research", since it shows that ANP chemo is almost certainly a waste of time and a danger to the patient; neither should they "build on this research", for essentially the same reasons.

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A study of antineoplastons fails to be published. Stanislaw Burzynski's propagandist Eric Merola whines about it. News at 11.

oracknows — Mon, 12 Aug 2013 01:00:44 +0000

A study of antineoplastons fails to be published. Stanislaw Burzynski's propagandist Eric Merola whines about it. News at 11.

Eric Merola alternates between offending me and making me laugh at his antics. Since it's been a couple weeks since I've written anything about the Houston doctor who claims to be able to do so much better against many forms of cancer than conventional medicine, I have to express a bit of gratitude to Mr. Merola for giving me today's topic for blogging. Mr. Merola, as you recall, produced two incredibly bad and deceptive movies lionizing that very same Houston cancer doctor as a brave maverick genius who's been kept down by The Man (i.e., the Texas Medical Board, the FDA, the National Cancer Institute, and the like).

Yes, I'm talking about Stanislaw Burzynski, MD, the Polish Prince (or is it Count?) who has been administering peptides he claims to have isolated from urine and later learned to synthesize to cancer patients since at least 1976 but hasn't bothered to actually demonstrate in a sufficiently rigorous fashion that they do what he claims they do or that they have significant anticancer activity in actual human beings. Instead, because various government entities quite understandably didn't want him administering unproven chemotherapy to cancer patients (and, make no mistake, his peptide therapy, which he dubbed antineoplastons" are chemotherapy, the claims of his lackeys, toadies, and sycophants like Suzanne Somers not withstanding), in the mid-1990s he submitted a bunch of clinical trials to the FDA and—miracle of miracles!—despite a profound lack of preclinical evidence got them approved. Of course, he had help. Rep. Joe Barton (R-TX) had been torturing the FDA for doing its job and trying to shut the Burzynski Clinic down. As I described, he orchestrated brilliant political theater in which seriously ill cancer patients, honestly convinced that Burzynski was the only person who could save their lives, gave tearful testimony in front of Barton's committee for the cameras. Meanwhile, the same patients marched and protested, providing more news fodder and putting more pressure on the FDA. So the FDA caved and approved 72 phase 2 clinical trials, even though they were, as Burzynski's lawyer put it, an "artifice."

However, even though Burzynski has dozens of clinical trials of antineoplastons against cancer registered at ClinicalTrials.gov but has not managed to publish even a single completed trial (yes, I know he's published case reports and preliminary reports on two trials, he has not published a completed trial), there is another investigator who has been doing a randomized clinical trial. His name is Dr. Hidaeki Tsuda of the Kurume University Hospital in Japan. He's an anesthesiologist, not a surgeon or oncologist; so I'm not sure why he's doing clinical trials of a chemotherapy agent. Whatever the reason, he is, apparently. I discussed Dr. Tsuda's trial, or at least what little we know about it from Eric Merola's second movie, in my review of that movie. Aside from the suspicion that always comes to me when a scientist decides to "publish by press release" (or, in this case to publish by appearing in a crank's movie, which is even worse), I have no way of judging the methodology and the results of the Dr. Tsuda's trial. All I know is that it was a randomized clinical trial in which patients with liver metastases from colorectal cancer were randomized to receive intra-arterial 5-fluorouracil (5-FU)by hepatic artery pump or 5-FU plus antineoplastons. One thing I noted is that intra-arterial 5-FU is a rather outmoded treatment that isn't used much anymore since the rise of combination regimens containing 5-FU plus other drugs, such as FOLFOX or FOLFIRI, but that's about all I can say about the clinical trial besides mentioning that we can't really tell whether the large increases in survival claimed in the movie by Dr. Tsuda are supported by his evidence.

Nor did I have any idea whether any progress had been made in getting the study published.

That's why I have to thank Eric Merola for updating me. In my e-mail this morning was a prolonged whine about—you guessed it—Dr. Tsuda's study. That led me to his movie Facebook page, where I found this notice, which was identical to the message in the e-mail:

The first ever independent randomized controlled clinical trial using Antineoplastons for the treatment of cancer at Kurume University in Japan—was rejected by Lancet Oncology this week. Even more interesting, the Japanese consulted with one of Britain's top oncology peer-reviewers to ghostwrite the manuscript, to make sure it was in perfect format for the Lancet.

The Lancet's reason for the rejection? It had nothing to do with the science or the study's design—but instead the Lancet simply said "we don't have enough room in our journal for this randomized study on Antineoplastons". In other words, the Lancet and the cancer establishment as a whole does not have any room for an oncology paper that involves cancer being cured by a paradigm-shifting invention, especially when the study is a randomized study which elevates "anecdote" to "proven"—since the randomized study is the industry's holy grail of clinical testing. If the Lancet had accepted it—they would have ironically been Lanced.

The fact is, Antineoplastons do not fit the Pharma mold, and therefore they are not allowed in. It's just the way our system works. Science is secondary to profit in today's market. Anyone who feels the need to come up with conspiracy theories to justify the ignorance toward Antineoplastons, just doesn't have a basic understanding of how our system works. This is just business 101.

Profit has and will always trump scientific truth. The entire industry is clever enough to realize that if Antineoplastons were allowed onto the market, their patents would eventually run out and they would eventually become a generic drug. And that can't be allowed to happen. If all companies within Pharma is allowed to make and sell Antineoplastons (as they do the antibiotic), who in their right mind would choose destructive and carcinogenic chemotherapy or radiation ever again? The industry knows this, and to protect the bottom line and Wall Street as a whole, Antineoplastons simply can't be allowed in.

However, the Japanese randomized studies WILL be published, but likely not in a journal that serves the industry and the owners who dictate the journals' content.

Stay tuned...

Eric, Eric, Eric, Eric, you are such a funny man. I really did laugh out loud when I read this. I can guess what almost certainly happened here, and—surprise! surprise!—it's not exactly what Mr. Merola believes to have happened. Most of us who regularly submit papers to scientific journals have on occasion had this experience, namely the editorial rejection, which is something that sometimes happens when one submits manuscripts to high impact journals. I recognize the language. It's nothing personal. It's no conspiracy. Basically, such journals get way more submissions than they can ever publish. In fact, they get so many submissions that they can't even send all of them out for review because they don't have enough peer reviewers. So such journals exercise a form of triage. Manuscripts that they deem either uninteresting, not particularly good, or not quite fitting in with the normal subject get a quick rejection and aren't even sent out for peer review. It happens all the time. It's happened to me. As a scientist or clinical investigator, you just get up, brush yourself off, and submit the manuscript elsewhere. (Indeed, editorial rejection can be a favor; the authors get a quick answer and can thus submit the manuscript elsewhere rapidly.) Heck, there was one manuscript of mine a few years ago that took me four journals and two years to finally get into print. Did I whine about it? No! (Well, maybe just a little bit; I was getting to the point where I thought I'd give up on ever getting the data published.)

What does Mr. Merola do? He alleges a conspiracy by the "cancer establishment" to suppress a cure for cancer. The hyperbole he uses is vintage Merola, so over-the-top that it really is hard to suppress a laugh when reading it. So Dr. Tsuda consulted with a peer reviewer to ghostwrite the manuscript? So what? If the topic is not interesting or the data are crap, its being well-written and rigorously adherent to the journal's format won't save it. The sense of entitlement dripping from Mr. Merola's little rant is quite simply, amazing.

Also amazing is his lack of understanding. He claims that antineoplastons "do not fit the pharma mold," which is actually ridiculous. They are, after all, chemotherapy. Sure, Mr. Merola denies it. Burzynski apologists deny it. Even Burzynski himself denies it. None of that makes it any less true that antineoplastons are chemotherapy. They are a drug. They even have significant toxicity! So, in actuality antineoplastons very easily fall comfortably within the paradigm of cancer chemotherapy. Or at least they would, if there were any compelling clinical trial evidence that antineoplastons have significant anticancer activity. That's the area where antineoplastons don't fit comfortably in the "big pharma paradigm." They are unproven and appear not to work. In a big pharma paradigm, they would fall into the category of a lead compound that didn't show much promise and was therefore abandoned.

Another curious thing happened yesterday. There appeared this Tweet:

Captain Morgan wannabe https://t.co/n2GyapAG6Q Why did TheLancetOncology NOT publish #Burzynski ? YOU suggested them http://t.co/Ag1VHH5VSN

— John Q. Public (@JohnQBull) August 11, 2013

The Tweet linked to in the Tweet above was this one:

@BurzynskiMovie @dianthusmed 1. Journal of Clinical Oncology. 2. The Lancet Oncology. 3. New England Journal of Medicine. (1/2)

— Paul Morgan (@drpaulmorgan) December 20, 2012

So basically, it appears that Mr. Merola likely transmitted suggestions for journals listed on Twitter to Dr. Burzynski and/or Dr. Tsuda, and the advice was taken. It's almost as though this particular Burzynski apologist thought that Dr. Paul Morgan meant that Dr. Tsuda's manuscript would definitely be accepted. Such naiveté is almost cute. Actually, it's painful to behold such basic ignorance about how scientific publishing works.

Of course, there is a way for Mr. Merola to demonstrate my educated guess about what really happened to be wrong. All he has to do is to answer a question and provide one bit of information. The question is, "Was Dr. Tsuda's manuscript sent out for peer review?" If the answer is yes, then all we need to see to determine if Mr. Merola's claim about the reason given for rejection of the manuscript is true is one simple thing. Show us the reviews from the peer reviewers. I bet that there aren't any, but if there are I would be very confident that none of them said that there was "no room" for Dr. Tsuda's manuscript in The Lancet Oncology.

It's really that simple, Mr. Merola. Put up or shut up. In the meantime, it's obvious what plan B is. (Hint: It won't be to submit to the New England Journal of Medicine or the Journal of Clinical Oncology.) It will be to find a bottom-feeding open access vanity journal that will publish basically anything as long as the authors pay. I'm not talking PLoS ONE here, but the dark side of the open access movement has been these "pay to publish" journals whose scientific standards are lax. That's where I see Dr. Tsuda's study being published, and that's where I see some of Dr. Burzynski's studies ending up. The reason is easy. They won't be able to make the cut to be published in respectable journals, traditional or open access.

Meanwhile, while I'm on the topic of Stanislaw Burzynski, it's been pointed out to me that another website by Burzynski supporters has arisen. It's called, unimaginatively, Burzynski Saves. Equally unimaginatively, it's chock full of the same tropes that Burzynski apologists are fond of, seemingly straight out of the mouth of Stanislaw Burzynski:

Dr. Stanislaw Burzynski has dedicated his life to saving cancer patients. He has saved many patients who were given no hope of recovery who are now living happy, healthy, cancer-free lives. Because his treatment involves innovative "out of the box" methods, the cancer fighting establishment, (including the FDA and the Texas Medical Licensing Board) and self proclaimed "skeptic" groups have spent the last 40 years trying to crush him and stop him from treating patients. The film 'Burzynski, Cancer is Serious Business' documents this well and can be watched on the media page. The Burzynski Part II film was released in 2013 and exposes more of this same treatment. We cancer patients and families and supporters have had enough and are fighting back. People engaged in the life and death fight for their lives should have the right to choose their doctor and their treatment without interference from special interest groups and government bureaucrats.

Burzynski supporters really need a new schtick. This one's getting really old. So is the schtick on the "Wall of Shame":

There are organized groups of people who call themselves "skeptics"who have made it their mission to try and destroy Dr. Burzynski. They attack and ridicule him and his cancer patients in blogs and articles and on Social Media. They mock any medical treatments they consider "alternative", chanting "where are the peer review articles?" (Peer review means that fellow MD's read articles presented for publication and decide if they are worthy of publication). Dr. Burzynski has presented, and published many studies and articles which the large medical journals refuse to print. Skeptics conspire to sabotage his medical practice by writing bad reviews on his clinic website, the Burzysnki Patient website & others under the WOT rating system so this symbol appears every time someone navigates to the page:

This is just as silly as Mr. Mercola's bloviation. The reason that medical journals have not published Dr. Burzynski's work is because (1) he almost certainly isn't trying very hard to be published and (2) his work just isn't up to snuff. Amusingly, however, whoever's behind the Burzynski Saves website honored me with a mention on the Hall of Shame. I wouldn't have it any other way. But really, I can't take all the credit. Bob Blaskiewicz will be envious!

On the other hand, the web design of the site is so horrendously ugly and its content is so bare bones that I can't believe it took them months to put it together. they have, after all, been promising this website since the earliest screenings of the second Burzynski movie in April. Surely they could come up with something better than this. Apparently not.

oracknows Sun, 08/11/2013 - 21:00

Categories

Medicine

The Lancet? Talk about aiming too high! That's like trying to submit a child's "What I did on my holidays" essay to the Booker Prize committee. Silly Eric.

As for Count Scamula, I don't think he ever had any intention of publishing. The excerpt from that book written by his former lawyer, that your "friend" posted, drove the last nail into that coffin. That indicated that he designed a "trial" for each type of cancer he was "treating" in order to get around FDA rules. If it is true then he's more disgusting and mercenary than I ever thought possible.

This study, however, was Dr. Tsuda's study, not one of Burzysnki's. Same principle, but it might not be as bad as Stash's phase 2 studies. Or it might. We don't know.

Interesting that they say they had someone ghostwrite the study. Pretty sure the Lancet (like all reputable journals) has an anti-ghostwriting policy. Perhaps that was the reason why it was rejected?

Mind you, it's possible they don't actually mean "ghostwrite". It's a term that a great many people misuse. Maybe the paper got rejected just because the study methods were hopelessly flawed.

the Japanese consulted with one of Britain’s top oncology peer-reviewers to ghostwrite the manuscript

Wait, what? A ghostwriter? Submitting a manuscript for publication under your name when it was actually written by someone else? Well well well. Grounds for rejection right there, for this and for future submissions.

I am puzzled by this job description of "oncology peer-reviewer". We are expected to believe in people who don't actually conduct oncology research, but sit in offices reviewing manuscripts from the people who *do* conduct the research (or moonlighting to write material designed for this profession of peer-reviewers). Evidently there is a ranking system within the profession, grading one as not only an "oncology peer-reviewer", but the top oncology peer-reviewer.

Shenanigans, sez I.

Curse the faster typing fingers of Adam Jacobs.

Whoa. The ghostwriter thing didn't even register because I gave them too much of the benefit of the doubt and assumed that they put his name in the list of authors. But if they did that, he wouldn't be a ghostwriter, would he? Good catch.

Maybe they just sent the manuscript to a British scientist to get the English checked? I know a few Chinese/Japanese groups who do this and then you wouldn't expect the UK scientists name on the paper, except maybe in the acknowledgments.

I think it's very difficult to learn anything from Merola's rant and would like to see this from a more reliable source than him before making too much of it. We are having to assume that both Merola and whoever gave him this information are being completely honest. We also have to assume that he hasn't misunderstood anything, that he knows what he's talking about. Given the rest of the content on the Burzynski Movie website, the reality may be quite different from what he has written.

@Annie

I've done some proofreading for a few of my Chinese friends - and that included making suggestions for grammar changes, clarity, etc.

That's basic editing. If they actually said 'ghostwrited' - that means something completely different from editing. It's reason to reject it, and anything else submitted by them - permanently, IMO.

A scan of the rejection letter/email from Lancet might tell us more than one quackadoodle holding a pity party for another.

My phd adviser did get one paper in the journal Science and one that did not during my stay there (alas, 'twas not my work that made it into Science), but other journals had been identified and a paper on the same research ready to submit to the lower-tier journal as a contingency. That and we always went to at least 1-2 research meetings yearly to present abstracts. And there were also papers we knew would never see the light of day in a top-tier journal because their content was not either broad enough in its audience or novel enough in its findings to merit such space. Those papers we sent to journals that were more specific to our research. I also noticed the same approach to submission of manuscripts by my postdoc adviser.

There was no conspiracy by some cabal of foes.

pardon...my end italics was supposed to come right after the second mention of Science:

A scan of the rejection letter/email from Lancet might tell us more than one quackadoodle holding a pity party for another.

My phd adviser did get one paper in the journal Scienceand one that did not during my stay there (alas, ’twas not my work that made it into Science), but other journals had been identified and a paper on the same research ready to submit to the lower-tier journal as a contingency. That and we always went to at least 1-2 research meetings yearly to present abstracts. And there were also papers we knew would never see the light of day in a top-tier journal because their content was not either broad enough in its audience or novel enough in its findings to merit such space. Those papers we sent to journals that were more specific to our research. I also noticed the same approach to submission of manuscripts by my postdoc adviser.

There was no conspiracy by some cabal of foes.

You are now my sworn enemy, Orac!

I find the conspiracy angle so very interesting and can't understand how it possibly persists. What does Mr. Merola think happens when those in on the "conspiracy" or their wives, husbands or children, get cancer? Do they just stay quiet and let them die, all in the name of profit? This conspiracy makes the mafia look like a leaky faucet, for not one of the millions involved has ever said a word.

So, rather than attempt to publish himself, Dr. B pushes a "surrogate" from Japan, who has been conducting this trial for how long exactly? As opposed to doing it himself, with the "decades" worth of data that he's collected?

Yet another means for Dr. B to resist publishing on his own, because now he can claim bias against his work in general (again).

If this isn't a general red flag for everyone, I don't know what is.

From the Lancet's editorial page:
"On submission to The Lancet, your report will first be read by one or more of the journal's staff of physicians and scientists. Our acceptance rate overall is about 5% and it is an important feature of our selection process that many papers are turned away on the basis of in-house assessment alone. That decision will be communicated quickly"

5% is the standard acceptance rate.

Salty Dog @13 -- you don't realize, do you, that all cancer doctors are childless, unmarried orphans.

Except for Orac, who is merely a large box of blinking lights.

His name is Dr. Hidaeki Tsuda of the Kurume University Hospital in Japan. He’s an anesthesiologist, not a surgeon or oncologist; so I’m not sure why he’s doing clinical trials of a chemotherapy agent.

A quick search through Orac's archives confirmed my recollection that when Burzynski was affiliated with a US university, way back when, he was in an anesthesiology department. Maybe a coincidence, maybe not.

the Japanese consulted with one of Britain’s top oncology peer-reviewers to ghostwrite the manuscript

There are several things about that statement which don't add up. First, the bit about ghostwriting, as others above have mentioned. But even more telling is the claim that the ghostwriter is "one of Britain's top oncology peer-reviewers". How do they know? Peer reviewers are often not named (some journals I am familiar with give reviewers the option to self-identify after the fact). One of the issues I see with the peer review system is the perverse incentives involved: as there are generally no explicit rewards for doing it well, those who do it well are "rewarded" only with getting more requests, while those who do it badly are "punished" by getting fewer requests. The inference that a top academic researcher is a peer reviewer is reasonable, but only the editors are in a position to assess how well he does reviews, and they aren't supposed to say.

OT: but are alt med loons announcing their plans for future world domination/ enlightenment EVER truly OT @ RI?**

Today MIke Adams announces his next moves upon the world stage via an audio clip:

-there will be a "content focus shift" at Natural News- he'll leave the activism and politics to others
- he will stick with food science and natural cures
- notes that there is a great increase in traffic
- two new venues SCIENCE.naturalnews and BLOGS.naturalnews
- the third venue will "rock the food industry"
-Robert Scott Bell will partner with NN and GCN radio
-Mike will have a show on GAIAM TV ( pay service)
-Mike will publish a food science book, 2014
- he'll create an Open Market for natural foods/ products
- Mike will provide answers that are currently being suppressed by you-know-who for you-know-what
- you've been lied to and "dumbed down"
-clean food leads to clear thinking
-it is his mission to "awaken humanity" who are enslaved by bad food, fossil fuel energy, media lies
-this spiritual awakening will occur after a time of tribulations and starvation
- the new higher awareness will usher in a revolution of consciousness wherein people will learn their true purpose
- there is life after death
- references to the Matrix and the Jedi
- missions cost money so visit the Store.naturalnews
- hip hop commercial for Store.com

** Minions and lurkers should be aware that I endured 41 minutes of MIkey so you wouldn't have to.. Oh, the things we do for love.
but you're WORTH it!. TOTALLY!

Some journals do list their peer reviewers - for example, JAMA (Journal of American Medical Association).

It's one of the things I discovered about Gary Goldman's padded CV (here: http://www.novaccine.com/gary_s_goldman.asp)

He bills himself as "serves as a reviewer for the following peer-reviewed journals listed with the National Library of Medicine:

Journal of the American Medical Association (JAMA)

Since JAMA publicizes their reviewers, I went and took a look at which year(s) he served as a reviewer. It was a single year.

I find the conspiracy angle so very interesting and can’t understand how it possibly persists. What does Mr. Merola think happens when those in on the “conspiracy” or their wives, husbands or children, get cancer?

The other amusing angle is the idea that whistle blowers won't reveal cures to win Nobel prizes, blackmail the conspiracy with evidence, or patent the treatment to get an edge over the other pharmaceutical companies. I've described this as a conspiracy that requires its members to be "selflessly greedy."

@Denice-

** Minions and lurkers should be aware that I endured 41 minutes of MIkey so you wouldn’t have to..

We should wash your feet with our tears of gratitude *weeps*

@Orac - The first bit of my comment was about the Japanese study, and the rest (about Stan) was garbled because I was RI-ing when I should've been asleep! Four hours of sleep and zero caffeine = brainsludge.

@Shay - oncologists are grown in vats in sterile, airless warehouses. They're government drones you see.

Wait. Wasn't the use of ghostwriters by Merck for some Vioxx studies part of what got them in hot water? And a frequent harping point for alt-medders?

Since JAMA publicizes their reviewers, I went and took a look at which year(s) he served as a reviewer. It was a single year.

That is consistent with being asked to review one paper, and doing it so badly that he was never asked again. The authors of the paper in question would not have known* that he was a reviewer, at least while the paper was under review.

Different journals handle it differently, of course. Some journals don't publish reviewer names at all. Some do it annually, as JAMA does, or in the preface of a conference proceedings. At the journal I am most familiar with, the editor will add an acknowledgment along the lines of, "I. B. Editor thanks I. M. Scientist and another reviewer for their assistance in evaluating this paper." In this case I. M. Scientist elected to self-identify and the other reviewer did not; both reviewers would be named if both elected to self-identify, and I. B. Editor would thank "two anonymous reviewers" if neither chose to self-identify.

*In some cases, particularly in relatively small fields such as mine, it is possible to guess the identity of the reviewer from the reviewer comments. For instance, if the reviewer wants you to cite a paper by Fulano et al. which was published in a conference proceedings book so obscure that your library doesn't have a copy, that is reason to suspect Dr. Fulano (or one of his co-authors) of being the reviewer in question. But it is quite common to guess wrong.

@Denice #18:

-clean food leads to clear thinking

And Mikey is the exemplar?

Minions and lurkers should be aware that I endured 41 minutes of MIkey so you wouldn’t have to.

I honestly don't know how you manage to stay sane under such a daily load.

@ elburto:

I aims to please.

@ Rich Wood:

Yes, Mikey is the reason I make sure I eat GMOs, pasteurised milk products and standardly raised fish / chicken several times a week.

And-
I have no idea why I am able to wade through this drivel and emerge unscathed- I believ I inherited my ancestors' high toleration for nonsense which stood them well in business for a few hundred years- of which I am aware- on two continents. It is a gift that my cousins and I share.

-btw- Supposedly, the other web woo-er is also enjoying a huge uptake in popularity ( which crashed his prn site) because he appeared on a Christian radio show and on public TV.

Is there no end to their power?

Does anyone else find it odd that Merola never brings up specific results of the study in his whiny rant? One would think that if the study showed anything of interest he'd have included some of the findings as evidence that this is a 'good paper.'

Does anyone else find it odd that Merola never brings up specific results of the study in his whiny rant? One would think that if the study showed anything of interest he’d have included some of the findings as evidence that this is a ‘good paper.’

Pick either (or both):

1. He doesn't understand the findings of the paper.
2. There were no findings of clinical interest in the paper.

But if they did that, he wouldn’t be a ghostwriter, would he?

Of course just because Merola is accusing the hapless Dr Tsuda of serious academic misconduct, does not mean we should believe him.

The part that stands out for me is the apparent admission that everything is just anecdotal:

"...especially when the study is a randomized study which elevates “anecdote” to “proven”..."

In some cases, particularly in relatively small fields such as mine, it is possible to guess the identity of the reviewer from the reviewer comments.

In VERY small fields like mine, the number of qualified potential reviewers can sometimes be counted on the fingers of one hand, and the author probably knows all of them personally. Hence, anonymous review turns into something of a joke.

You gotta wonder about the "top peer reviewer" claim, given all the cutting edge, world renowned scientists that alt med toutsthat nobody in the scientific community has ever heard of.

Also, Mr. Merola needs to spend 4 hours with a publishing scientist who will explain the entire clinical trial process, from hypothesis to publication, in minute detail. That's how long it took someone to explain it to me--on the entire drive from Boise, Idaho to Washington state. It's unbelievably complex, and one session like that would leave Merola a tad red faced at his presumption.

Biomedical communicators who contribute substantially to the writing or editing of a manuscript should be acknowledged with their permission and with disclosure of any pertinent professional or financial relationships.

http://www.amwa.org/files/About%20Us/AMWA_PositionStatement_Contributio…

But, see, ghostwriting is bad only when Big Pharma does it. Of course.

If a researcher and colleagues aren't very good at organizing data and putting together a coherent paper, is it unethical for them to obtain the services of someone with good paper-writing skills to do the job for them (and not list this person as a co-author)?

I can't imagine such a scenario occurring very often, since the ability to write a good paper should be part of every research professional's job description. And it's not all that difficult to put together a paper in the proper "format". Just read some articles that have been published in the journal to get an idea of how they're organized.

In any event, the fact that Tsuda (et al?) bothered to get help and still got rejected by Lancet Oncology probably speaks to a lot more than just writing flaws.*

*In Antivax-Land, they'd be busy checking the past of all possible peer reviewers to drum up damning conflicts of interest. Maybe that will be Merola's next revelation.

If a researcher and colleagues aren’t very good at organizing data and putting together a coherent paper, is it unethical for them to obtain the services of someone with good paper-writing skills to do the job for them (and not list this person as a co-author)?

Not at all. But this contribution must be acknowledged somewhere in the paper, along with any COIs, or it’s considered ghostwriting. (See pages 2-3-ish in International Committee of Medical Journal Editors.)

Doesn't everybody know Bobby Vinton is *the* Polish Prince? (Although I prefer (the late) Ed Blazonczyk and the Versatones for that gangnam polka style, being a Chicagoan.)

Sorry, brain freeze @ 31. I meant Merola should be explained the process from hypothesis through clinical trials through drug approval. Quite a deal.

@Xplodyncow: hear, hear! Thank you for posting the AMWA and ICMJE positions. I am a former AMWA member credited with "editorial assistance" on a number of papers. All pharma support was explicitly spelled out. I would really like to know the true story behind the peer-reviewer/ghostwriter.

I love alt pharm's continuous refrain of "Big Pharma's poisoning you for money!" You know what? So are Burzynski and Tsuda. I'm currently on FOLFOX for colorectal cancer, and I would much rather have the side effects I'm experiencing from 5-fu and oxaliplatin over the unquenchable thirst and other things I've read on The Other Burzynski Patient Group.

My body is slowly recovering from the grand mal cringe induced by the design of that page. Was the design serious and sincere, or was it given the charming, home-built design in a diabolical ruse to appeal to the "less sophisticated"?

Do I sound like an uppity a-hole for even saying that?

If it is purposefully bad, I must say the motivational picture with the horse jumping into the surf and the caption "Sometimes, You Need To Become Your Own Hero" was a truly brilliant touch.

Bob Blaskiewicz:

You are now my sworn enemy, Orac!

Get in line, no cuts allowed.

@Dangerous Bacon (#34)

It's not unethical for authors to seek the help of professional medical writers when publishing a paper, provided that the role of the writer is disclosed (either as a co-author or in the acknowledgements section of the paper). If the writer's role is not disclosed, then it's ghostwriting, which is unethical.

And actually, it does happen quite often, particularly in pharma-sponsored studies. Less often in academic-led research. It's not just about whether the authors lack the skills to write a paper (although that's sometimes an issue), it's also about whether it's an efficient use of their time. Clinical investigators are often more highly paid than medical writers, and also take longer to write papers, so it's simply more efficient for the paper to be written by a professional writer.

Next time you're looking at a medical journal, just have a look at the acknowledgements sections of the papers. You might be surprised how often you find someone acknowledged for writing assistance.

Thanks for clearing up "ghostwriting" ethics.

Maybe I could make some dough on the side cleaning up the writing I see in medical journals (though I really don't need any, seeing as how my supplemental shill income from Big Pharma runs into the hundreds of thousands of dollars annually). ;)

@ Skeptical Slug
You made me spit tea on my screen with the "grand mal cringe". That so aptly describes portions of my day. I thank you, and I shall plagiarize you. :)

@ Dangerous Bacon
I read papers and my fingers and toes curl at some of the, um, turgid prose and complete lack of clarity. The nuns (damn them) taught me better than that and I just can't help myself--I NEED TO EDIT!!

Janet -- ditto. I'm reviewing an IRB submission right now and I have a feeling the only reason I was asked to be a co-PI is because I have decent English skills.

Merola's use of the statement "Profit has and will always trump scientific truth" would be comically ironic if it weren't for the said reality of all the desperate people who have paid Burzynski so much money.

No wonde Science refused to publish my paper on nematode behavior...it was a conspiracy by Big Fruitfly to keep nematode research from the public!

Merola's claims are really quite laughable. I find it incredible that he seems to think that a journal I mentioned in a tweet in a response to a question about where Burzynski might publish his trial results would somehow automatically publish trial results of an antineoplaston study, no matter who conducted that trial.
That Tsuda and his department of anaesthesia are involved in researching cancer therapies is rather bizarre, but there does seem to be a track record of doing so as a PubMed search for "Tsuda antineoplaston" yields 15 results. The last publication, however, dates back to 2005. Most are laboratory studies but there are a couple of case reports and small case series. Certainly nothing that comes close to showing any beneficial effect from antineoplaston therapy. The journals previously published in are not in the same league as "Lancet Oncology" which, it seems, only accepts around 5% of submitted articles for publication. Many submissions will not be of sufficient quality to even make it to the peer review process. It would therefore be useful to see a copy of the rejection letter (almost certainly an email) posted online. I strongly suspect that the paper was judged not good enough to even pass first sift, let alone get to peer review. Of course, this won't stop Merola spouting more accusations of Big Pharma suppression but would at least show that a paper had been submitted in the first place. There are those of us who doubt that such a submission was made.
Clinical trials in Japan are supposed to be registered much in the same way that they are in other countries. There are 3 registers in operation in Japan. All three are searchable in English. There are no registered trials of antineoplastons, and nor have there been in the nearly two years that I've been interested in Burzynski's activities and the antineoplaston saga.