Bad science Bioethics Cancer Medicine Quackery Skepticism/critical thinking

Clínica 0-19 and IDOI: Not making DIPG history in Monterrey (part 4 of 4)

Orac has finally located the abstract published by Dr. Alberto Siller and Alberto Garcia, who are selling intra-arterial chemotherapy for the deadly brain tumor DIPG. Let’s just say that he’s…less than impressed by the results. Shades of Burzynski!

A couple of months ago, I was shocked to discover a quack cancer clinic in Mexico. Let me rephrase that. I wasn’t shocked to discover a quack cancer clinic in Mexico, which unfortunately is rife with them. Rather, I was surprised at the quackery being plied at this particular cancer clinic and a hospital in Monterrey. The clinic is Cliníca 0-19; the hospital is Hospital Angeles; and the doctors are Dr. Alberto Siller, a pediatric oncologist, and Dr. Alberto Garcia, an interventional radiologist, who make up Instituto de Oncología Intervencionista (IDOI), which also has a slick website declaring it to be ” leader of the intra-arterial brain tumors procedure and recognized for its Diffuse Intrinsic Pontine Glioma (DIPG) treatment.” DIPG, as you might recall from all my blogging about another cancer quack, the Polish expat in Houston named Dr. Stanislaw Burzynski, is a particularly nasty brain tumor that is highly lethal. I’m revisiting the topic because I have new information, specifically, the data that Drs. Garcia and Siller claim

In fact, it was the way that Drs. Siller and Garcia reminded me of Burzynski that first got me interested. Children from Australia, Europe, and the US were traveling vast distances to spend hundreds of thousands of dollars on an unproven treatment, inspired by stories of seemingly miraculous results spread on Facebook pages and websites like Making DIPG History in Monterrey. Credulous journalists portray the crowdfunding efforts of families of the children with DIPG being taken to Monterrey as heroic battles to save their child’s life by taking that child to undergo “experimental therapy” not available in the child’s home country and not paid for by the government or insurance companies. We saw it for Addy Joy Sooter. We saw it for Annabelle Nguyen, whose parents didn’t just pay hundreds of thousands of dollars but found their family trapped in Monterrey for weeks, paying $2,500 a day for ICU care for their daughter when her condition deteriorated. (A medical flight back to Australia would have cost them a quarter of a million dollars.) When I analyzed what Drs. Siller and Garcia were doing, I was horrified to learn that it was a “make it up as you go along” concoction of up to a dozen chemotherapy agents injected both into the arteries leading to the brainstem and intrathecally (into the cerebrospinal fluid) plus an unknown, unproven “immunotherapy” that appears to be some form of made-up dendritic cell therapy.

And the evidence? Let’s just say that Burzynski had more evidence for his antineoplastons than Drs. Garcia and Siller have for their “intra-arterial chemotherapy” for DIPG. No, I’m not kidding. Burzynski might not have published anything resembling a completed clinical trial, but he did publish 42.5% of a clinical trial. He later published a very unconvincing clinical trial, and one of his acolytes published an unconvincing clinical trial. And the Clínica 0-19 crew? At the time I wrote about their “intra-arterial chemotherapy,” they hadn’t published anything. It was even worse than that. Dr. Siller was often quite dismissive of skepticism about his protocol and would make the excuse that he was too busy taking care of patients to do a clinical trial or even to publish his clinic’s survival statistics.

Then I learned that that wasn’t quite true. Dr. Siller and Garcia had presented their results in an abstract at a Mexican conference not long before I wrote my posts. However, I couldn’t find the actual abstract, search as I might. Yesterday, though, a reader let me know that the abstract can now be found, having been published as Immuno Mexico 2018, XII Congress of the Latin American Association of Immunology and XXIII Congress of the Mexican Society of Immunology. The abstract is on page 369 and entitled Super-selective intraarterial chemotherapy in the primary management of diffuse intrinsic pontine glioma: 2-year experience from an institution in México by Alberto García, Alberto Siller, Paola García, and Sixto Trejo.

A dodgy abstract

I’m going to reproduce the entire abstract because that will make it easier to discuss:

Introduction: Diffuse Intrinsic Pontine Glioma (DIPG) is an aggressive tumor in the pons with a median overall survival of 9 months, ≥90% of patients won’t survive 2 years after diagnosis.

Super-Selective Intraarterial Chemotherapy (SSIAC) is a delivery method that allows higher drug concentrations at the tumor site while exhibiting only mild systemic toxicity due to relatively low levels of the agent in circulating blood.

Aims: The presented study focuses on our experience treating patients diagnosed with DIPG using SSIAC with a non-protocolized, individualized set of Chemotherapeutic drugs.

Experimental strategies: Eligible subjects are under 18 years of age, with a radiological diagnosis or proven DIPG biopsy, excluding those whose tumor extends beyond the pons or with the presence of metastasis.

Initial evaluation and follow-up consist of MRI, PET/CT and Lansky play-performance score.

Results: From March 2016 to April 2018, 62 patient’s clinical and radiological conditions were evaluated and treated by our team with intraarterial chemotherapy. A median of 7 intraarterial procedures per patient were performed. With age ranges between 2 and 17 years, 8 years on average, 22 male and 40 female, with a median of survival after the diagnosis of 489 days and counting.

The follow-up range for these results has a median of 6 months. A median of Lansky score 60% before treatments and a median of 80% after treatments.

45 are with stable disease, none with progression of the disease and 2 of them in remission, all presenting response to treatment. 17 deaths related to treatments prior to our intervention.

Immunological parameters were taken into account to perform the treatments.

Conclusions: Given the inconsistent efficacy of radiotherapy and the limitations of systemic chemotherapy, innovation in adaptable therapeutic methods is a necessity

Patients with DIPG can benefit from being treated with SSIAC, resulting in radiological improvement and better quality of life.

My reaction? Simple: That’s it? These are the fantastic, miraculous results that justify charging families? Let’s explain why these results are not that impressive, at least as published in the abstract. (Maybe their poster or talk had more information, but somehow I doubt it.) First, though, let’s look at the description of the treatment itself, which is basically bare bones. It’s not unexpected that Drs. Siller and Garcia don’t list the chemotherapy agents used; they never do. Indeed, getting that information out of them has proven to be…challenging. I only obtained such information because a medical oncologist from the UK asked for some information and one patient’s family provided me with a list of drugs used, and my information was not necessarily generalizable because Dr. Siller touts his “individualization” of treatments, which basically means making it up as he goes along. Oh, wait. He objects to that characterization? Until he can describe how he picks one set of chemotherapy drugs for one patient and another for a different patient using a scientific rationale, I will continue to characterize this concoction this way. More odd, no mention of “immunotherapy” is made. The abstract says “immunological parameters were taken into account,” but there’s no way of knowing what the heck that actually means. In any event, this entire conference is an immunology conference. Without the immunotherapy there wouldn’t have been much reason for this abstract even to be submitted to this particular meeting.

One part I found depressing to contemplate was where the number of treatments patients undergo was listed: A median of seven intra-arterial treatments per patient. That’s a median of seven general anesthesias, at least for children too young to cooperate under local anesthesia with sedation; seven angiography procedures, each with its attendant risks of bleeding, unnecessary radiation dosing, kidney failure due to the intravenous contrast dye, and the actual chemotherapy injected. What is not mentioned in this abstract is whether these seven intra-arterial treatments include seven intrathecal treatments as well, given that many of the descriptions I read from parents involved intrathecal chemotherapy as well. (Remember, Parker Monhollon’s cascade of complications began after the insertion of an Ommaya reservoir, a catheter system for infusing drugs into the cerebrospinal fluid.)

But what about the reported results. I find it interesting that the authors didn’t say how they analyzed survival (Kaplan-Meier?) Did they use an intent-to-treat analysis to estimate responses and survival? The authors estimate a median survival of 489 days for their treated patients. That’s basically 1.34 years. That’s basically 16 months. The most frequently quoted median survival for DIPG treated conventionally is less than a year, but with a a fairly wide range among studies, as summarized by the DIPG Registry:

The prognosis for patients with DIPG is very poor, with most studies indicating a median survival of less than 1 year from diagnosis. In a review of clinical studies, median overall survival ranged from 4-17 months, with median progression-free survival of 3-10 months. Overall survival at 1 year ranged from 14-70%, at 2 years from 0–25%, and at 3 years from 0-10%.[1]

Considered this way, an estimate of 16 months for median survival is at the high end of existing reported studies. It’s superficially impressive but nothing that much out of the ordinary, and that’s if you actually believe that Drs. Siller and Garcia calculated median survival correctly, a contention that, given their history, I am understandably quite skeptical of.

Cause of death: Anything but the cancer or intr-arterial chemotherapy?

What raised my eyebrows even more was the part where Drs. Siller and Garcia stated that there were 17 deaths “related to treatments prior to our intervention.” Oh, really? How was it adjudicated for each patient who died that the cause of death wasn’t tumor progression or complications from IDOI’s treatment? Now that, if anything, is a determination that would need to be made by an outside doctor, because doctors actually using an unproven “experimental” treatment like that of IDOI can be automatically assumed to be too invested in the therapy to be sufficiently neutral to make such a determination. That doesn’t go just for this treatment, but any experimental cancer treatment. Let’s just put it this way. Any of those 17 patients who received even one round of the IDOI treatment should be counted for purposes of determining median survival. My guess is that, were that to be done, the survival of this group of patients would not be so impressive. Worse, as has been the case before when Dr. Siller has said that he prefers that patients who come to Clínica 0-19 have not had radiation and requires that the patient be off steroids prior to his treatment.

Then there’s the issue of “stable disease.” Stable disease means disease that isn’t progressing. Let’s just say that I don’t have a lot of faith in IDOI to use appropriate imaging interpretation to decide whether a given DIPG is progressing or not. I discussed this very issue in the case of Annabelle Nguyen, whose tumor, the parents were told, had “only shrunk by a small percentage” and shown “less contrast.” As I noted at the time, here again, we see another aspect of the story reminiscent of Burzynski patients like Amelia Saunders. Burzynski told her parents that cysts forming in the tumor were a hopeful sign that her DIPG was responding to therapy. I had to explain that they probably weren’t. Solid tumors, as they grow, not infrequently outgrow their blood supply, so that the central part of the tumor dies and liquefies, which can look more cystic than the rest of the tumor. At this point in the story, I’m getting the same vibe, a lot of handwaving and representing findings as more hopeful than they are, and the same thing could have been happening here. Also, tumors remodel as they grow, and unless the shrinkage is very clear, small differences in size could be misinterpreted as tumor shrinkage when in fact the tumor has not changed. Nowhere have I seen evidence that a competent neuroradiologist is interpreting these scans, and I’ve noted that IDOI often orders PET-CT scans instead of the preferred imaging modality, MRI. Dr. Paola Garcia, for instance, is on the IMED Hospitals Oncology Service and appears to be a palliative care doctor.

It was also pointed out to me that the IDOI changed its website, adding this about its treatments for DIPG:

A European Society of Pediatric Oncology (SIOPE) and the International Society of Pediatric Oncology (SIOP) collaborative report, which gathers records of Diffuse Intrinsic Pontine Glioma (DIPG) and was published in July 2018, reveals that the average survival rate in more than 700 cases is 11 months.

As of mid-2018, IDOI has treated 67 patients with an average age of 9 years diagnosed with DIPG. After treatment, the median survival was 18 months. Just over 70 percent of the patients had over 1 year of survival and almost 20 percent more than 2 years of survival. The Institute continues to advance and improve.

IDOI stands out as an institution by virtue of its statistics, since it has almost 10 percent of the SIOPE and SIOP patient registry, and for obtaining more favorable patient outcomes on average.

So this sounds as though they added five more patients to the mix, to bring the total up to 67.

In any event, as I’ve described before, although these numbers sound at least better than average compared to the usual results obtained treating DIPG, there is a lot of reason to doubt that IDOI and Clínica 0-19 have made any sort of breakthrough. For one thing, again, given the general shadiness of Dr. Siller’s excuses about why he hasn’t published his results or protocol in the peer-reviewed literature or allowed international DIPG experts from Australia to visit Monterrey, audit his results, and help him set up a clinical trial to test whether his protocol actually improves outcomes for DIPG patients compared to the standard of care.

Selection bias a-go-go

Another major potential confounder is that there could be considerable selection bias in the patients treated by Drs. Siller and Garcia; i.e., patients whose families can bring them to Mexico are not like typical DIPG patients. First, they have families who are either wealthy enough or sufficiently involved and ambitious enough to raise a lot of money very fast to pay for expensive treatments. Such children are likely to be healthier and in better shape from a general health standpoint. Next, the treatment involves long international flights to Mexico every few weeks for treatment. All other things being equal, a child who can tolerate such frequent travel to a distant city is likely to have less advanced disease than a child who cannot. Finally, there’s the requirement that a child receiving this therapy be off steroids for several months. A general use for steroids in neuro-oncology is to control the brain swelling around the tumors. The skull is a closed space, and the swelling caused by brain tumors can cause a dangerous increase in intracranial pressure that can, if allowed to progress too far, kill quickly. Thus, any patient who can tolerate being off steroids for prolonged periods of time, even a period as short as a few weeks, must a smaller and/or less aggressive tumor. Ditto any child who can go without radiation therapy long enough to get to Mexico and receive this intra-arterial chemotherapy.

I hope I’ve adequately explained now why, taken in the context of these observations, the doubt about whether Drs. Siller and Garcia know what they’re doing when it comes to constructing Kaplan-Meier survival curves, and all the potential confounders, I’m less than impressed by their results, which are likely due to selection bias and inappropriately excluding patients who “died of their previous treatment” from survival calculations.

Growing the cancer quackery business

Yet Drs. Siller and Garcia continue to try to expand their business. I was just informed by a Polish reader that IDOI and Clínica 0-19 appear to be targeting Polish families of children with brain cancer, just like Stanislaw Burzynski did (and, as far as I know, still does). Examples include Marysia Mituła, whose family is raising money via Facebook and Just Giving because their daughter was diagnosed with glioblastoma:

From Maria: “My name is Maria Mitula. I am 5 years old. Few weeks ago, I started having big headaches and tummy aches. I went with my mummy to the doctor and he told me I need to go to the hospital to get some important tests done. After speaking to the lady doctor at the hospital she told me to lie down on a special bed so she can have a better look at me. The adults call that bed tomography (TK) but for me it was like bed from space. Mummy and daddy said they will be in the next room and they will be looking at me through the window so I can lie down without moving for a while. It is not so easy when you are 5 years old and you don’t know what will happen. Maybe it will actually take me to space?! I started hearing a voice speaking to me but there was no one else in the room. Maybe it was a magical bed after all. I was lying there and I was doing my best not to move. It all took about 5 minutes.

After this examination Mummy and Daddy came to me. They were smiling but I could feel they were very sad. Like my daddy is saying sometimes ‘sometimes we are crying inside without the tears on the outside’. I think this is how he was feeling. I didn’t know that the lady doctor said to mum and dad that I have a tumour. A brain tumour.

Then there’s Martynka Kontra, also from Poland, who is being treated in Monterrey. Meanwhile, I recently saw in the news the story of Cameron Truesdale, an Irish boy with DIPG whose family took him to Monterrey but who, unfortunately, died last week. Meanwhile, more fall into the crowdfunding maw every month.

The more I look at Clínica 0-19, IDOI, and what Drs. Siller and Garcia are doing, the more I hear echoes of Stanislaw Burzynski, but worse. The quackery IDOI engages in involves repeated invasive procedures and even less evidence than Burzynski was ever able to muster with no evidence of a desire to undertake a clinical trial. Until I see these rogue doctors publish their actual protocol, welcome international DIPG experts to Monterrey with open arms and cooperate fully with them to determine their true results using rigorous statistical methodology, I call quackery. Until rigorous statistical methodology by oncologists and statisticians who know what they’re doing show that IDOI DIPG patients survive sufficiently longer than average to raise the possibility that it’s not just due to confirmation bias and/or more indolent disease in their patients, I call quackery. Even if Dr. Siller’s and Garcia’s patients do survive longer, unless they agree to submit their protocol to a proper clinical trial to determine whether their treatment is superior to the current standard of care I consider them profiteers.

Somehow, though, I don’t think I’ll be holding my breath waiting for them to do these things.

The complete series

  1. Clínica 0-19 and IDOI: Not making DIPG history in Monterrey (part 1 of 4)
  2. Clínica 0-19 and IDOI: Not making DIPG history in Monterrey (part 2 of 4)
  3. Clínica 0-19 and IDOI: Not making DIPG history in Monterrey (part 3 of 4)
  4. Clínica 0-19 and IDOI: Not making DIPG history in Monterrey (part 4 of 4)

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

9 replies on “Clínica 0-19 and IDOI: Not making DIPG history in Monterrey (part 4 of 4)”

First, they claim that their treatment has a 100% success rate (for their dubious definition of success) if you ignore the cases that they claim were too badly damaged by prior treatments. Yeah, that one trips the BS meter. Try to at least make your lies plausible, people.

Second, even with their cherry-picking of relatively healthy patients, they only boost median survival by seven months (from 11 to 18). Are those extra seven months (even if they are real, which is doubtful) worth the price the parents are paying?

Congratulations, Dr. Garcia and Dr. Siller. You have the dubious achievement of making yourselves look worse than Stanislaw Burzynski.

Their “abstract” seems to consist if “We did stuff, and it worked.” I am, amazingly, even less convnced than before.

Doesn’t hurt that they started with children with tumors under a certain size and that weren’t already metastatic. That alone could have been a reason for continued survival.

Can a patient with stable disease be considered to be “in remission”?

If not, then the math in the abstract is off. (62 total patients – 17 deaths = 45 patients. What about the “2 of them in remission”?)

If so, I’m not sure how they can say that “stable disease” = “response.” (To me, “remission” implies a partial/complete response, not SD, but I am no physician.) Then again, if it is in abstract that was presented at a conference, it must be true, right? Right?! Ugh.

@ Xplodyncow:

Because it isn’t getting worse? If you don’t die, alties may count that as a cure.


At any rate….
In other woo news….OT or not

AS you may know,
I’ve been featuring how woo-meisters and anti-vaxxers are carrying on because they are being “censored” by facebook, you tube, twitter, google, wikipedia etc
WELL, I have it on good authority ( Ari Melber, an hour ago) that posting BS on the internet may finally become more difficult as he surveys the case of Alex Jones getting banned and sued by families of victims he lied about.
There are quite a few internet entrepreneurs who should be quaking in their Ferragamos / Manolos.
Let’s hope.

I loathe the type of people who would take advantage of families at such a desperate time in their lives. It’s absolutely despicable. These doctors have talked themselves into believing their own hype at these childrens’ expense. It’s very upsetting to read about what these kids have been through, but this series is a perfect example of how easy it is to fall prey to unproven, untested treatments when facing a terrifying diagnosis.

At the expense of making myself sound immature, may these doctors get pinworms and hemmorhoids at the same time (wormmorhoids!).

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