The atomic structure of laetrile, which does not cure cancer but might poison you.
Note: Some of you have probably seen a different version of this post fairly recently. I have a grant deadline this week and just didn’t have time to come up with fresh material up to the standards of SBM. This left me with two choices: Post a “rerun” of an old post, or recycle something. I decided to recycle something for reasons explained in the first paragraph of this post.
As I was deciding what to write about this week, I realized that, surprisingly, there is precious little on Science-Based Medicine about the granddaddy of modern cancer quackery, Laetrile. Given that the final nails were placed in the coffin of the quackery that was Laetrile more than 30 years ago in the form of a clinical trial that didn’t show a hint of a whiff of benefit in cancer patients, many of our younger readers might not even know what Laetrile is. But, as I explained when I wrote about Stanislaw Burzynski’s early years in the 1970s, which happened to be they heyday of Laetrile, in cancer quackery everything old is eventually new again, and Laetrile is apparently soon to be new again. True, it’s never really disappeared completely, because, again, no matter how discredited a cancer quackery is, someone somewhere will keep selling it and some poor cancer patient somewhere will be taken in. In any case, it occurred to me that we at SBM have discussed the politics of Laetrile. Indeed, Kimball Atwood once referred to it as the “the most lucrative health fraud ever perpetrated in the United States.” Moreover, Kimball makes a convincing case that the Laetrile controversy was an important precursor that laid the groundwork for advocates of “alternative medicine”—or, as it later became known, “complementary and alternative medicine” (CAM) or “integrative medicine—to successfully lobby for the founding at the National Institutes of Health of what later was named the National Center for Complementary and Alternative Medicine (NCCAM). However, there didn’t appear to be a post dedicated to discussing Laetrile itself, and something happened last week that allows me to rectify that situation.
So how is Laetrile about to become new again? Remember our old buddy Eric Merola? He’s the guy who made two—count ’em—two conspiracy-laden, misinformation-ridden, astonishingly bad bits of “great man” propaganda disguised as documentaries about a Houston cancer doctor peddling unproven cancer treatments and charging his patients tens and even hundreds of thousands of dollars for the privilege of being under his care while receiving this magic elixir, known as antineoplastons. Over the last several months, ever since he unleashed Burzynski: The Sequel on an unprepared and uninterested world, Merola has been hinting about his next project. Given Merola’s involvement in Zeitgeist: The Movie and his primary role in throwing together two hack propaganda pieces that were so blatantly worshipful of Burzynski that Leni Riefenstahl, were she still alive and able to see them, would have told Merola to cool it with the overheated hero worship and portrayal of his movie’s subject as a god-man a bit, I knew his next movie would be more of the same. I also knew it would not be about Burzynski.
What it would be about, specifically, remained a mystery, however, until about two months ago, when it was revealed that it would be about Ralph Moss, who, it turns out, is one of the foremost promoters of Laetrile and was intimately involved with putting pressure on Congress to push for clinical trials of Laetrile, even though there was nothing that would resemble convincing preclinical evidence to justify such a trial. It also turns out that he was one of the original “Harkinites,” described by Dr. Atwood thusly:
His degree is in classics, but he has styled himself as an expert in cancer—mainly “alternative” cancer treatments. Moss was a long-time member of the NCCAM’s Cancer Advisory Panel for Complementary and Alternative Medicine (CAPCAM). In 2004 he wrote a glowing eulogy for rabid Laetrile promoter Michael Culbert, who had been a vice-president of the Committee for Freedom of Choice in Medicine, the major Laetrile advocacy organization. Moss has recently written approvingly of Mexican cancer clinics that continue to peddle Laetrile, although he is careful to add that “there are no reliable ‘miracle cures’ for cancer in Tijuana or elsewhere.”
Somehow, I’m not surprised that this man is the topic of Eric Merola’s new movie. Apparently he’s found a new hero to worship other than Stanislaw Burzynski.
Last week, the YouTube channel for Merola’s movie, Second Opinion: Laetrile at Sloan-Kettering dropped four (!) trailers on an unsuspecting (and even more uninterested) world. My first reaction was: Did I read that right? Laetrile? I guess Merola must need a new conspiracy, his having so totally had his posterior handed to him over and over and over again over Stanislaw Burzynski. One wonders if Burzynski is about to lose his very own personal Leni Riefenstahl. (Hey, if Burzynski and Merola can Godwin the skeptics critical of Burzynski, I can return the favor, at least in jest.) Besides, the comparing Merola to Leni Riefenstahl does a profound disservice—to Leni Riefenstahl. After all, Leni Riefenstahl had serious talent, as vile as the cause to which she dedicated her talent was. Eric Merola? Not so much.
But let’s take a look at the trailers. I must admit, Merola’s production values are a bit better than they were. At least that robotic-sounding announcer doesn’t appear to be there anymore, although the cheesy music is, as are the annoyingly artificial, film school artsy camera angles, overcooked for straight documentary interviews, are still there. In the first one we see:
Of course, as I mentioned in the beginning of this post, Moss has been pushing Laetrile since the 1970s, complete with an obviously nonsensical conspiracy theory about how the leadership at Memorial Sloan-Kettering Cancer Center (MSKCC), where he worked as a medical writer, had suppressed evidence that it worked. Back then, Laetrile was the biggest cancer quackery going, way, way bigger than anything Stanislaw Burzynski had done, bigger than just about any bogus cancer therapy I can think of. You can see it from the NEWSWEEK cover from the period at the beginning of the clip, which proclaims that perhaps 70,000 Americans with cancer had crossed the border to Mexican quack clinics (well, it didn’t use that word, but it’s accurate) to get Laetrile. I must admit that I had never personally delved into some of the primary literature about Laetrile, but Merola’s movie gave me an excuse to do it. It’s quite revealing.
At least Merola got it right to describe Moss as a science writer at MSKCC. Depending on when he’s telling it, Moss has—shall we say?—inflated his credentials. For instance, in his book The Cancer Industry, Moss apparently represented himself as assistant director of public affairs, implying that an executive-level position made him privy to the innermost workings of MSKCC. Oddly enough, at least one contemporaneous account of the controversy also refers to him by that title. It turns out that he was nothing more than, as Merola reports, a science writer, being employed at MSKCC from 1974 to 1977 and receiving a “summary discharge.” (In other words, he was fired. In fact, he was fired the day after Second Opinion, who are discussed below, was trumpeted to the public, as this summary of the incident from 1977 published in Science describes.) His position was characterized as “ranked at the lower end of the pay scale.”
It strains credibility to believe that Moss could really have known much, if anything, about the high level machinations he claims to know about, even though a quote from the same account suggests that he did. Whatever the true case, other than Moss, the principals of the Sloan-Kettering incident are no longer alive and can’t confirm or deny Moss’ account. None of this stops Moss from spinning a tale of suppression of research by the powers-that-were at MSKCC to hide evidence that Laetrile was active against cancer, going so far as to say that all the leaders of MSKCC who stated that there was no evidence that Laetrile (or, to be more scientifically accurate, amygdalin) had significant anticancer activity were lying, accusing them of a cover-up. Why would MSKCC want to cover up evidence of a highly effective cancer treatment? As is the case with Burzynski, Merola, letting Moss tell his story unfiltered, never explains this convincingly.
In any case, Moss and a group of employees from MSKCC “leaked” documents which, or so they claimed, “proved” that Laetrile/amygdalin worked in animal models. This group, known as Second Opinion, wrote a report “blowing the whistle” about the cover-up. If these clips are to be judged, it’s going to be another hilarious bit of paranoid conspiracy mongering. Particularly amusing is this clip:
What was your reaction when you watched this? (Seriously. Watch it. It’s less than 2 minutes.) First, we have the unlikely tale of Moss meeting with all the top administrators of the Sloan-Kettering Institute to find out their views on Laetrile. Next, we’re treated to a bizarre story in which Moss claims to have met with Lloyd J. Old, MD, the vice-president of the Sloan-Kettering Institute at the time. Dr. Old is claimed to have said to Moss: “You want to know where we get all of our new ideas?” Old supposedly handed Moss a book, saying, “Here, this is the Bible.” That book, allegedly, was the American Cancer Society’s book, Unproven Methods of Cancer Management. (Sadly, it’s a book the American Cancer Society no longer publishes.) Basically, it was a list of cancer quackery, a compendium of brief articles the ACS published in its journal from the 1950s to the early 1990s describing modalities considered to be cancer quackery (although even then the ACS didn’t use that word), with brief explanations and reviews of the evidence showing why they were quackery.
My first thought was that Moss’s account was the proverbial pile of fetid dingoes’ kidneys. But then I wondered. Is it possible that Dr. Old might have been having a little fun with a clearly gullible young science writer who had probably by that time developed a reputation around MSKCC for believing in Laetrile, that he might have been pulling a credulous young writer’s leg, and messing with him a bit? I wonder. Certainly the story doesn’t sound particularly convincing, but if something like that did happen, I can totally picture Moss falling for a prank like that hook, line, and sinker. Who knows? As an aside, I happen to have collected quite a number of articles from the ACS Unproven Methods list. Some of this stuff I hadn’t heard of before. One of these days I’ll have to march through parts of the list. It’s perfect SBM material that can be done any time. In any case, I did find the last entry on Laetrile in the list, published in 1991, to be most helpful for this post.
Next up is another clip:
Now it’s not enough that Moss claims to have been buddies with the vice president of the Sloan-Kettering Institute. According to him, he was also buddies with Robert Good, MD, the president of the Institute himself. If Moss is to be believed, he was discussing writing a book with Dr. Good. Whether you believe this or not, Moss tells of an incident of scientific fraud that occurred that Dr. Good had to deal with, involving a researcher working for him named William Summerlin. This was a very famous case of scientific fraud in the 1970s, in which Summerlin convinced people that he could transplant skin from black mice onto white mice. If true, this would have been a major breakthrough because of the difficulty in getting transplants from genetically unrelated organisms to “take.” Supposedly, Summerlin accomplished this feat by culturing the skin in special solutions. In reality, he used black ink markers to darken the fur. It’s hard to believe anyone could get away with a trick that simple and obvious, but for a while Summerlin did, all while working for Dr. Good, who, impressed with his work, became his mentor and saw to his promotion. Ultimately Summerlin was found out, and the story made national news. (Indeed, an excerpt from a news report on the incident by Walter Cronkite himself is included in the clip above.) Moss says that this scandal broke the same day he learned he was getting a job at the Sloan-Kettering Institute. I suppose he tells this story to imply that Memorial Sloan-Kettering Cancer Center played fast and loose with science at the time. He denies it, and maybe Moss didn’t intend it that way, but you can be sure that Merola did.
So why, according to Merola, did Moss go on to become a Laetrile warrior and hardcore promoter of unproven “alternative” medicine? (Excuse me, that’s redundant.) Here is the blurb:
One of his first assignments was to write a biography about Dr. Kanematsu Sugiura, one of the Center’s oldest and leading research scientists as well as the original co-inventor of chemotherapy.
While meeting with this iconic scientist to pen a biography on his 60-year career at Sloan-Kettering, Moss discovered that Sugiura had been studying this “quack remedy” in laboratory mice, and with unexpectedly positive results. Shocked and bewildered, Moss reported back to his superiors what he had discovered, only to be met with backlash and denial from Sloan-Kettering’s leaders on what their own leading scientist had found.
Fueled by respect and admiration for Sugiura—Ralph W. Moss attempted to publicize the truth about Sugiura’s findings. And after all diplomatic approaches failed, Moss lived a double life, working as a loyal employee at Sloan-Kettering while also recruiting fellow employees to help anonymously leak this information to the American public—through a newly formed underground organization they called—“Second Opinion”.
There’s no doubt that Dr. Sugiura was a pioneer in chemotherapy research. (His obituary was published in Cancer Research, and, trust me, Cancer Research doesn’t do that for just any cancer researcher.) Were it not for his involvement in Laetrile research in the mid-1970s, people like Moss and Merola would revile him as one of the people who contributed to the “poisoning” of patients.
Here’s also where other sources were useful, because a lot of what’s on Merola’s website is the same old sorts of misinformation that he previously used in the service of Burzynski. The negative clinical trials were rigged not to work. He claims Laetrile “tested positively” in preclinical studies but that those results were covered up. Dr. Sugiura’s work was claimed to have been suppressed, causing Moss to form his “Second Opinion” group, which ultimately got him fired from Sloan-Kettering. At least, it sounds as though he were fired; it’s not clear. Whatever the case, it’s the same old conspiracy tropes that one finds swirling around Burzynski and his unproven cancer treatments. No wonder Merola was attracted to the topic. Of course, Laetrile was studied. It didn’t work.
So what about the “positive” results?
First, what is Laetrile, which is often interchangeably called amygdalin or “vitamin B-17,” even though it’s not a vitamin? Basically, “Laetrile” is the trade name for laevo-mandelonitrile-beta-glucuronoside, a substance allegedly synthesized by Ernst T. Krebs, Jr. in the 1920s. It’s chemically related to amygdalin, a substance found naturally in the pits of apricots and various other fruits. Again, most proponents of Laetrile for the treatment of cancer use the terms “Laetrile” and amygdalin interchangeably. Apparently amygdalin was tried as an anticancer agent as early as 1892, but was abandoned because it was ineffective and toxic, because it can break down into glucose, benzaldehyde, and hydrogen cyanide. (Yes, that cyanide.)
Like a lot of cancer quackery, the rationale for Laetrile has shifted over the decades. In the 1950s, Kreb claimed that cancer tissues are rich in an enzyme that causes amygdalin to release cyanide, which would destroy the cancer cells. Supposedly noncancerous tissues are protected by another enzyme. (Yeah, right.) Later, Krebs claimed that Laetrile/amygdalin is a vitamin (B17) and, of course, cancer is due to a deficiency in that particular vitamin. Other claims have shifted, from Laetrile being a cancer cure to being able to “control” cancer to being a cancer “preventative.” I see this in Merola’s website, where in one passage he claims that the reason the clinical trial in the 1980s showed no anti-cancer activity due to Laetrile is because it arrests cancer growth and shouldn’t be expected to work in advanced cancer. (Funny, the quacks in Tijuana never had any problem claiming Laetrile could cure advanced cancer.) I also note a great similarity with how evidence for antineoplastons is presented. For example, check out this story from the article on Laetrile on Quackwatch about Dr. Ernesto Contreras, one of the most—shall we say?—most active Laetrile doctors in history who ran a clinic in Tijuana in the 1970s:
By 1974, Dr. Contreras stated that he was seeing 100-120 new patients per month, with many more patients returning to obtain additional Laetrile. Patients typically were charged $150 for a month’s supply. Contreras acknowledged that few of his cancer patients were “controlled” with Laetrile. While admitting that 40% of the patients displayed no response, he claimed that 30% showed “most definite responses” to the drug. However, these statistics may not be reliable. In 1979, he claimed to have treated 26,000 cancer cases in 16 years. Yet when asked by the FDA to provide his most dramatic examples of success, Contreras submitted only 12 case histories. Six of the patients had died of cancer, one had used conventional cancer therapy, one had died of another disease after the cancer had been removed surgically, one still had cancer, and the other three could not be located [5].
Sound familiar?
The National Cancer Institute carried out a retrospective case review of case records of patients treated with Laetrile by practitioners all over the country in 1978. There were 67 case records submitted as “best cases.” Of these, the NCI could find evidence of a possible complete response in only two patients and of a partial response in four. Other reviews of case histories presented as the “best evidence” for Laetrile (such as this one) found no convincing evidence that it might have anticancer activity in humans.
The final nail in the coffin of Laetrile (unfortunately not the final nail in the coffins of Laetrile patients) was a clinical trial published in the New England Journal of Medicine in 1982, along with an accompanying editorial. Merola, not surprisingly, doesn’t like this trial and disingenuously criticizes it:
As explained in “Chapter 4″ of the “DVD Extras” of this project, the human clinical trials conducted were not designed based upon standard protocol by designing the human trials around the previous successful animal studies, which showed that Laetrile prevented cancer, stopped it’s [sic] ability to spread, and relieved pain. Instead, they chose patients who had exhausted all previous forms of therapy, and gave them Laetrile. The average survival time for these patients in the Laetrile studies was only 4.8 months.
They also did not conduct a randomized trial, instead they conducted a non-randomized Phase II study, with no basis for comparison to see how Laetrile fared against chemotherapy and/or radiation. Given that chemotherapy and radiation were unable to help these patients, it would be highly unlikely that Laetrile would have had any positive effect, since Laetrile was only proven in lab studies to prevent cancer and keep it from spreading, when administered in the early stages of cancer. Therefore, it would make sense that Laetrile would be ineffective within a group of late stage cancer patients.
Yes, this was a non-randomized phase II trial, but it was done that way because given the politics of the time it almost certainly couldn’t be done any other way, as the accompanying editorial noted that the trial had to “pick its way through a minefield of formidable obstacles.” It couldn’t be controlled, randomized, or blinded. As Dr. Arnold Relman described:
It avoided ethical objections by giving Laetrile to all patients (with fully informed consent, of course), but selecting as subjects only those for whom there was no known effective treatment or in whom standard treatments had already failed. On the other hand, it blunted the anticipated criticism from the Laetrilists by selecting patients only in good general condition and by including fully a third who had never received chemotherapy or radiotherapy and therefore might be considered particularly good candidates for Laetrile.
Yes, this was very much like trials of quackery like the Gonzalez Therapy, ten years before the founding of the office that would later become the National Center for Complementary and Alternative Medicine (NCCAM) and 20 years before the travesty of ethics and science known as the Gonzalez trial. In any case, 175 patients with advanced cancer were treated with Laetrile plus a “metabolic” therapy commonly used with Laetrile at the time. To blunt criticisms of the Laetrilists that the investigators weren’t using high enough doses, the investigators treated patients with a “standard” Laetrile dose and what they referred to as an “extremely high dose program.” The end results showed only one patient who met the criteria for a partial response to therapy, and that sounds as though it wasn’t real. The patient had stable tumor size for five weeks, then moved to another location, where his initial tumor measurements met the criteria for partial response. His tumor then progressed. Thus, this was a questionable, transient response. There was no evidence of prolongation of life based on historical controls and no evidence of tumor response, but there were several cases of cyanide toxicity. The bottom line was that there was not a hint of a whiff of any evidence that Laetrile had antitumor activity.
But what about the mouse studies by Dr. Sugiura? As our good friends at the American Cancer Society point out, at least a dozen sets of animal experiments were performed at seven institutions with a variety of transplantable tumors treated with Laetrile from different sources, including from the key organization at the time promoting Laetrile, the McNaughton Foundation. In all experiments that were properly blinded and used objective tumor measurements, there was no evidence of anti-tumor activity due to Laetrile. Then:
In 1975, Laetrile advocacy groups claimed that positive results had been obtained at Memorial Sloan-Kettering Cancer Institute. These experiments were not blinded and were based on visual estimation, rather than quantitative measurement, of metastatic growth. Further double-blind experiments that used an objective bioassay for metastatic growth were negative.
That would be this study, which concluded, “we do not have evidence to support taking amygdalin to clinical trial, although other considerations may require that one be conducted.” Those “other considerations” were lobbying and political pressure due to the activities of pro-Laetrile activists and pseudoscience-friendly legislators.
Science published a news/opinion article about Laetrile at MSKCC in 1977 that laid out the history of MSKCC’s testing of Laetrile. Some key passages:
Stock makes clear that he does not say Sugiura’s results are wrong. But he and Good believe that an important test for choosing between Sugiura’s results and his colleagues’ was a blind experiment in which the mice were injected by others and Sugiura, who did the pathology, was not told which mice were treated with laetrile and which were the controls. Although the system was the same as that of Sugiura’s first six experiments, in this case laetrile turned out to possess no anticancer activity.
If the inference is made that the results with the 14 tumor systems are more likely to be true, Sugiura’s results are an anomaly. No immediate explanation is available, but perhaps none is necessary: anomalies are a common feature of the scientific landscape and there is only time to resolve the most interesting.
This is very, very common. Even the best scientists forget that not just clinical trials need to be blinded. Animal experiments should, ideally, also be blinded, just as clinical trials are, particularly if measurements are being made that are the least bit subjective, such as a human being counting and estimating the volume of metastases. These days, we have much more objective systems, such as imaging systems that can calculate tumor volume based on volumetric estimates, which make blinding not always as critical. Still, many of these systems rely on humans to judge where the edges of the tumors are; so even then blinding is important. Here’s another telling passage, quoting the scientist whose records the Second Opinion Group managed to get a hold of:
Second Opinion charges that Sloan- Kettering has suppressed some results favorable to laetrile. The group has obtained certain data from the files of Elisabeth Stockert, a member of the Sloan- Kettering team, and claims that they show a positive anticancer effect for laetrile. Stock says he did not suppress the results, because he didn’t know about them, and would not have included them if he had because they are uninterpretable. Stockert agrees; the study, she says, was not a proper experiment but a preliminary investigation which had to be abandoned when she went to Paris for 5 months.
In other words, Second Opinion cherry picked some preliminary experiments that, according to the Science article, were “uninterpretable,” and ignored all the negative experiments.
The bottom line is that Eric Merola has once again yoked his horse to a scientific and medical loser, an even bigger loser than Burzynski has been. Laetrile was discredited a long time ago. His complaints about the lack of a randomized clinical trial are, as usual, whining. To get to a good randomized clinical trial, one needs convincing preclinical evidence in the form of cell culture and animal models, for which none existed for Laetrile, and a preliminary clinical trial. Well, the preliminary clinical trial was done, and it was negative. When that happens, in the normal course of drug development, the drug is abandoned; it is not taken to a larger randomized clinical trial. In fact, given the spectacular failure of Laetrile in animal studies and the NEJM clinical trial in 1982, it would be unethical to do another trial.
I do see one purpose to Merola’s resurrection of the rotting, apricot-scented corpse of Laetrile. Burzynski is currently trying to duplicate the political activism of the Laetrile supporters of the 1970s. Let’s hope he doesn’t succeed, because the Laetrile activists like Moss came the closest of anyone to persuading Congress to legalize cancer quackery—at least before Senator Tom Harkin persuaded Congress to create the NCCAM. It is, however, not surprising that Merola would be as attracted to Ralph Moss as he was to Stanislaw Burzynski, nor it is surprising that Burzynski is currently making similar arguments to the ones made by the Laetrilists in the 1970s.