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Last week’s post about Clínica 0-19, a clinic in Monterrey, Mexico that offers what is often incorrectly characterized as a “revolutionary” and “experimental” new therapy for diffuse intrinsic pontine glioma (DIPG), a deadly cancer of the brainstem that disproportionately affects children, certainly provoked a reaction. Indeed, I don’t recall a reaction like this since the early days of my posting about Stanislaw Burzynski. At Clínica 0-19, the founders of Instituto de Oncología Intervencionista (IDOI, or the Institute of Interventional Oncology), pediatric oncologist Dr. Alberto Siller and interventional neuroradiologist Dr. Alberto Garcia, offer poorly-described and ill-defined intra-arterial chemotherapy to the brainstem combined with an even less defined and described “immunotherapy” to the desperate parents of children suffering from DIPG, charging patients $30,000 a treatment and requiring ten or more treatments, performed mostly at nearby Hospital Angeles.

Reading the stories of desperate families, mainly from the US, UK, and Australia, selling possessions, cars, and houses and going to social media and crowdfunding to try to come up with the huge sums of cash required to pay for the treatment provoked a sickening feeling of déjà vu, given my long experience writing about the Burzynski Clinic and antineoplastons. So, too, did the form many of the news stories about families of children with DIPG taking them to Monterrey remind me of news stories about families of Burzynski’s DIPG patients going to Houston in that, with but a precious few exceptions, they uncritically described the treatment offered by IDOI as “experimental” therapy or an “experimental” protocol, with only a passing mention, if any mention at all, of the criticism directed at these doctors. Let’s just put it this way. To be an experimental therapy, the treatment has to be in active testing in the lab and in clinical trials, and the doctors running IDOI are not doing any research. They’re just treating and charging patients, excusing themselves from even the most basic requirement of publishing their own survival and recurrence statistics by saying they’re “too busy saving lives.” But it’s worse than that. In March, in response to credulous stories in the Australian press about “miraculous results,” the Cure Brain Cancer Foundation (CBCF) in Australia offered to sponsor a DIPG expert to travel to Monterrey to examine what Drs. Siller and Garcia are doing at Clínica 0-19 and Hospital Angeles and see if they might be on to something, further offering to fund a clinical trial of the IDOI protocol if its expert determined Clínica 0-19’s results were promising. The answer consisted of more excuses and stonewalling. It’s now four months later, and, as far as I’ve been able to ascertain, Dr. Siller still hasn’t taken CBCF up on its offer.

I didn’t expect to be writing about Clínica 0-19 again so soon, but, as I mentioned above, the response to last week’s post rather mandates that I do. I received emails from several people. Amusingly, naturopath Kim Beauchamp was very unhappy with my characterization of her Making DIPG History website first, mistakenly, as part of Clínica 0-19. That was an error I was happy to correct. However, when she then objected to my characterization of her site as a “fan site,” calling it “libelous,” I changed the text to point out her use of the quack Miranda warning and mention how I thought naturopathy was quackery. (As I wanted to tell Not-a-Doctor Beauchamp, be careful what you ask for.)

More importantly, I received some emails from parents who took their children to Monterrey to treat their DIPG. Uniformly, they were unhappy with me. I also received an email from a person who had a relative whose parents had taken her to Monterrey and were much less impressed with Drs. Siller and Garcia. Finally, I learned a lot more about the chemotherapy and immunotherapy being used. Let’s just say that I was less than impressed.

It was all too much for one post, even accounting for Gorski levels of logorrhea. So I decided to divide my discussion in two. First, for this post, I’ll primarily focus on what I’ve learned about what Drs. Siller and Garcia actually do and why it is unsupportable scientifically or ethically. Next week or sometime later in July, I’ll finish by making a trilogy out of this (the way I did for Rigvir), the last post focusing on individual patient testimonials. Let’s just put it this way. Clínica 0-19 is now on my radar screen, the way Stanislaw Burzynski showed up on my radar screen seven years ago. I will be paying attention, and these three posts, of which this is the second installment, are likely to be just the beginning.

The mystical magical intra-arterial chemotherapy offered by Clínica 0-19

If you read my last post, you’ll know that I spent a fair amount of verbiage trying to figure out just what it was that Drs. Siller and Garcia were offering. They don’t publicize, publish, or even mention online exactly what chemotherapeutic agents they inject into the arteries leading to the brainstem. Indeed, on the IDOI website under “medications,” this is all they say:

As part of our protocol we use an array of different drugs. Some of the drugs are helpful for cytotoxic chemotherapy, molecular targeted therapy, and immunotherapy. All these drugs are used in a particular sequence and dosage. All drugs are perceived as an important parameter in a pre-established time of infusion. All these conditions are extremely important to get the results we have. We worked for decades in order to improve these techniques and this is how we differentiate ourselves from others.

Notice how they don’t mention even a single example. One might speculate, for example, that temozolomide might be one of the chemotherapeutic agents used. Although it doesn’t improve overall survival over radiotherapy alone, there is evidence that it improves survival in a subset of DIPG patients. In existing clinical trials of intra-arterial chemotherapy, such as the one at Johns Hopkins Hospital, they use melphalan. In contrast, from various reports from parents I’ve discovered that Drs. Siller and Garcia use up to 11 different chemotherapy agents, with no rationale or algorithm for how they are selected.

An oncologist also contacted me after my post and let me know that there had been reason in the past for her to contact Drs. Siller and Garcia and ask them what they use. The response revealed that they used cisplatin 1 mg, cetuximab 15 mg, doxorubicin 0.25 mg, and Avastin 12.5 mg. Cisplatin is a platinum-containing chemotherapeutic agent that interferes with DNA replication in fast-dividing cells, while doxorubicin is an anthracycline antibiotic that inserts itself into DNA and interferes with replication as well. Cetuximab interferes with the activity of the epidermal growth factor receptor, and is most commonly used for cancers like colorectal cancer and head-and-neck cancer. It has not been shown to prolong survival in DIPG, at least when combined with irinotecan. Avastin, of course, is an antiangiogenic agent (a drug that inhibits the ingrowth of new blood vessels by the tumor to feed itself). Results of a phase II trial testing it plus irinotecan against recurrent DIPG (which, let’s face it, is what most patients going to Clínica 0-19 have) were disappointing as well, with no responses.

I also can’t help but note that these doses are very low. For instance, a typical dose of Avastin is between 5-15 mg/kg every three weeks. For a typical child weighing 10-20 kg, we’re looking at a dose that could be as much as 20 times lower than recommended. (That’s leaving aside the fact that Avastin has not been FDA-approved for use in children, as far as I can tell, thus showing that Drs. Siller and Garcia are not being entirely accurate when they say they only use FDA-approved medication.) Similarly, it’s been pointed out to me that the doses of doxorubicin and cisplatin are even lower. For instance, a dose of cisplatin in children for brain tumors off-label is around 60 mg/m2. (This is body surface area, or BSA, based dosing.) A typical three year old girl at the 50th percentile would be 95 cm tall and weigh around 14 kg, requiring a dose of 26 mg. Similarly, doxorubicin is normally dosed in children between 35-75 mg/m2. You get the idea. These are very low doses. Now, an argument can be made that if you’re injecting it intra-arterially into the tumor you can achieve drug levels in the tumor high enough to do the job; that’s kind of the idea. However, does anyone think that Drs. Siller and Garcia actually did the difficult pharmacokinetic and pharmacodynamic studies in animals and humans necessary to determine these lower doses? I certainly don’t. Personally, I think they just made it up. If they did do the work and didn’t publish the results, then that’s arguably just as bad because they’re keeping important information secret. But, again, I’d be shocked if Drs. Siller and Garcia did anything resembling the rigorous preclinical work to determine their dosages.

Basically, when you sum it up, the results of clinical trials of chemotherapy for DIPG have been very disappointing. So, basically, what we have here are several chemotherapeutic agents with no documented significant demonstrable activity against DIPG. I also note that this oncologist strongly suspected that Dr. Siller was not revealing the entire regimen, noting that either that was the case or they have incredibly expensive suppliers for their medication. (Personally, I agree but also wouldn’t be surprised if this were the current regimen, with a generous markup charged to patients.) She also noted that even what was revealed was considerably more toxic than palliative radiation therapy, which is undeniably true. (Review articles that I read noted a fairly high incidence of bleeding into the tumor as a complication of some of these chemotherapy agents.) Add to that the utter lack of transparency in which chemotherapy agents are used and especially how Dr. Siller determines which chemotherapy agents to use for which patient and in which order, and my skeptical antennae are twitching faster than ever. Dr. Siller claims there’s an algorithm by which he makes these decisions, but won’t reveal it. To me, that suggests, more than anything else, that he’s just making it up as he goes along and that his use of the “personalized” nature of his regimen as an excuse as to why it can’t be easily studied in a clinical trial is akin to the same excuse that homeopaths make for their woo.

And then, another person who’s had interaction with Dr. Siller wrote me and gave me a more comprehensive list dating to last year. The list includes trade name, generic name, and the process that the drug inhibits:

Zaltrap (ziv-Aflibercept) (VEGF, angiogenesis)

Laedemab (Nimotuzumab) (EGFR)

Camptoop (Topotecan) (Topoisomerase)

Opdivo (Nivolumab) (PD-1)

Avastin (VEGF, angiogenesis)

Trixilem (Methotrexate) (dihydrofolate reductase)

Jevtana (Cabazitaxel) (Microtubule inhibitor)

Yervoy (Ipilimumab) (CTLA-4)

Adriamycin (Doxorubicin) (topoisomerase, histone eviction)

Blastolem (Cisplatin) (DNA replication)

Wow! Now that’s throwing everything but the kitchen sink at the tumor with no rhyme or reason. Some of those drugs are old and not very expensive (e.g., methotrexate, doxorubicin), but some of them are new and damned expensive (e.g. Opdivo). Some of them are also redundant. Why, for instance, are two drugs needed to target VEGF? Why Opdivo, which is a PD-1 inhibitor that targets T-cells? Also, the more drugs you add, the more chances there are for adverse reactions, unexpected interactions, and synergistic toxicity. My jaw dropped when I read this full list. Also remember that this list is a year old. Who knows what Dr. Siller has added to his witches’ brew?

Yes, it is possible that these chemotherapy agents, particularly injected right into the arteries leading to the brainstem, could produce responses in terms of tumor shrinkage, but only at the cost of significant toxicity. Let’s also not forget that these are children, some of whom are toddlers. Every time they undergo intra-arterial chemotherapy, they have to undergo general anesthesia, meaning that they undergo repeated anesthesias. Let’s also not forget that each time they undergo intra-arterial chemotherapy, a large catheter has to be introduced into the femoral artery and guided to the proper arteries under fluoroscopy. The children also undergo repeated lumbar punctures to introduce the drugs intrathecally (into the cerebrospinal fluid that bathes the brain and central nervous system).

So what’s different about this protocol? The answer I find on the IDOI FAQ isn’t exactly persuasive and likely wouldn’t be persuasive to anyone treating cancer patients from a science-based perspective:

IA treatment has been tried before what is the difference this time round?

Certainly the treatment by this route (intra-arterial) has been tried in the past and still they do it in certain places. What makes it different is the preparation, mixing, dosing and sequential administration of the different drugs that make up our treatment model. We also use the intrathecal route to administer certain drugs.

Translation: It’s our magical protocol that we won’t tell you about. Trust us.

Here’s the thing. It’s entirely possible that infusing toxic chemotherapy and targeted therapy directly into the arteries feeding the tumor and into the cerebrospinal fluid could cause a DIPG to shrink. The problem, however, is the counterintuitive experience over many decades that tell oncologists that initial tumor response/shrinkage does not necessarily mean improved overall survival. Certainly shrinkage is better than no shrinkage or growth through treatment, but many have been the trials where tumor shrinkage initially did not result in prolonged survival. That’s why clinical trials in which overall survival is determined in the treatment group are essential. Add to that the fact that there are outliers who survive longer—sometimes much longer—than the original prognosis given and that clinics like Clínica 0-19 are subject to survivor bias, in which we hear about the patients who do better than expected but not so much (more like nothing, really) about patients who do average or worse than expected, and the need for Dr. Siller to publish his survival data becomes a moral and scientific imperative. If his survival statistics are significantly better than historical controls, he might be onto something, or he might not. Remember, the patients he treats, particularly those from Australia and the UK, can all withstand repeated long trips to Mexico, which suggests that they are in better shape physiologically than the average DIPG patient, and they come from families who either can afford the $300,000 in charges or can raise that much money rapidly. One would expect that these patients as a group would be likely to do better than average anyway.

But what about the immunotherapy?

One of the patients’ parents who wrote took umbrage at my speculation that the “immunotherapy” that Dr. Siller was using might be some sort of poor man’s CAR-T therapy. CAR-T is the latest flavor of immunotherapy in which the patient’s T cells are harvested, genetically modified to attack the patient’s tumor, and then reinfused. The only reason I speculated that is because I couldn’t find anywhere else what on earth Dr. Siller might be doing. Fortunately, this parent, as angry as she might have been at me and as much as she thought she had a “gotcha” moment, filled me in:

Furthermore, their immunotherapy is also not done at the clinic. The blood is sent to a lab at the University of Monterrey, the white and red blood cells are separated and dendritic T Cells are added, which are closely monitored by published Doctor Cristina Rodriguez and her chemists. Once matured, which takes 7 days, they are transported to Hospitale Angeles where they are infused back into the child’s body during their treatment.

The name Cristina Rodríguez had come up before in some of my reading, but I hadn’t been clear if there were a connection to Clínica 0-19. Knowing her name, I was able to do some searches. First, I found out that there is no faculty with that name at the University of Monterrey. However, there is a María Cristina Rodríguez Padilla, PhD at the University of Nuevo Leon who looks as though she fits the description based on her CV and university webpage, which show her to be Professor and Chairman of Department of Microbiology and Immunology, and Head of the Laboratory of Virology and Immunology, School of Biological Sciences Universidad Autonoma de Nuevo Leon. Her lines of research include:

Trinomial: Immune-Cancer-Virus

Biotechnological Development of biological response modifiers for diagnosis and therapy

Formulation and implementation of biologicals

Yes, this sounds like the right Prof. Cristina Rodríguez, although I can’t be 100% sure. Certainly she appears to have the right qualifications.

But dendritic cells? Seriously? This is 1990s technology. I remember reading about dendritic cells as a new means of delivering immunotherapy when I was a graduate student in the 1990s. It was the hot new thing nearly a quarter century ago. Basically, dendritic cells are antigen-presenting cells. Their main function is to process antigen and then present it on their cell surfaces to T cells. This makes them a crucial component of the mechanism by which vaccines generate specific immune responses. Methods for exploiting dendritic cells to treat cancer generally include either stimulating them to accentuate their anticancer activity or to remove them, stimulate them in a test tube outside of the body, and then reinfuse them. There are a variety of strategies for achieving this stimulation. Without knowing exactly what it is that Rodríguez is doing, it’s hard to figure out how likely she is to be successful.

Dendritic cells as a strategy for cancer immunotherapy are still under study, but results have been disappointing, with classic objective tumour response rates rarely exceeding 15%. More importantly, there are very few data on dendritic cells as a potential treatment for DIPG. The most recent study I could find was this one from Spain, which concluded nothing more than that it was possible to use dendritic cells to generate a DIPG-specific immune response. That’s not to say that combining some form of dendritic cell vaccination with other therapies might not end up being effective, but in DIPG at least this strategy is in its infancy, with what can at best be described as potential proof-of-principle studies published. Using dendritic cells along with intra-arterial chemotherapy without a lot more clinical and preclinical data is not justified scientifically. In fact, it’s downright unethical.

As for Prof. Rodríguez-Padilla, I was hard-pressed to find anything on PubMed that resembles what she is supposed to be doing with dendritic cells and DIPG. There are no publications by her on DIPG, and there is only one publication by her involving dendritic cells and AIDS. She isn’t even the first author, either. She does have papers on immunotherapy and cancer, though. (Oddly enough, she’s also co-author on an article about the psychological effects of group hypnotherapy on breast cancer patients during chemotherapy.) Still, I’m hard-pressed to figure out why she would be doing this sort of work for a dubious clinic like Clínica 0-19, although I can speculate. I also find it very telling that there is no mention of this work that I can find anywhere on her university webpages or other webpages about her. It’s almost as though she wants to keep her collaboration with Drs. Siller and Garcia on the down low. (Either that, or I picked the wrong Cristina Rodríguez, but I highly doubt that I did.) That’s why I’m thankful that that patient’s mother told me about her. I might never have found out who was doing the “immunotherapy” for Clínica 0-19 and IDOI and what that “immunotherapy” is.

The cost of everything

All of this unproven therapy with 10 or more chemotherapeutic and targeted agents plus an unproven do-it-yourself homemade immunotherapy cost a lot of money—a hell of a lot of money. This became apparent from a post in a Facebook group, DIPG Support and Awareness:

Here we learn:

In order to get a list of medications used you will need to set up a call because the treatment is tailored to the child’s tumor and needs, and your child’s medical history. He uses multiple drugs and it’s the delivery method that is important as well, not just the medications used. The medication is based around the tumor. Again, if you are wanting to know more about treatment protocol you will need to call the clinic and set up a conference call.

Well, I already know that I’m not at all impressed by Dr. Siller and Garcia’s protocol. It’s very much like Burzynski’s use of targeted therapy and chemotherapy: He throws everything but the kitchen sink, without expertise or thought, at the tumor, and it sure does look as though that’s what Dr. Siller does too.

Now here’s the pricing. It’s a veritable racket, as you will see:

Below you will find a post with the most recent info on the treatment and pricing by by [sic] a DIPG mom who inquired with the clinic and kindly shared the info in a post for other parents. Generally parents have said to expect each treatment and trip to be around $20,000. Please read: “Dr Siller and Dr Garcia have been doing IA treatment for 18-20 years on various brain tumors. Different drugs are used for different tumor types and makeup. It is not a one size fits all situation. The newest drugs are producing more advanced results. Over the years he has had children with different brain tumors reach NED. The longest one is at 5 years and they are in observation still. They do regular visits with their local Onc and Dr Siller and Garcia, They [sic] are in school full time and not on steroids. With the current program of drugs for DIPG, and immunotherapy, there is a lot of promise to be able to reach NED. They are currently working with their local hospital to have it accept out of country insurance. As in they will work with your insurance company for payments.This has not gone through yet but they are hoping it will soon. Pricing: 15-17K USD. Breakdown – $7500 for professional fees for Dr Siller and his entire team in total. $3500 negotiated for the drugs with the pharmacy. Total of $11000 USD to be paid up front prior to appointment confirmation. After that $5000-6000 for ICU/Procedure/MRI before procedure to be paid to hospital. Immunotherapy: typically would begin after multiple cycles and off steroids for a few months. This is an IA and cervical lymph node infusion. They require 200 ml of blood to get dendritic and other cells. This varies from IOZK immunotherapy. This is $10,000 USD and is through the local immunotherapy clinic. You initially will plan for 4-6 weeks of stay. If you are deemed well you can leave as soon as possible however you must be fully functional. After the initial visit you will return every 3 weeks, for the $15-17K every time until NED is reached. For IA and Immunotherapy together you can expect to spend about $33,000+ (that’s just for treatments) each time (£25,000).

NED, as I discussed last week, means “no evidence of disease.” Look at the charge list, though. Look at how much it resembles the Burzynski model: Cash up front on the barrelhead, or, as this post puts it:

Medication is administered to the brain stem Basilar & Femoral arteries. The procedure is performed minimum every 17 days. An MRI will be taken before each IA procedure to allow them to see how the tumor has reacted and tailor the following treatment. 2 insertions are made, one in the groin and one in the back. Children are taken straight to ICU after then moved into a private room. The amount of nights/days in the hospital will depend on how your child recovers. Children also have a pediatric doctor assigned to them while in the hospital. You will need to have access to “I-translate” as most of the nurses and hospital staff don’t speak English. You pay for every little thing you need, everything. You are required to pay a deposit when you arrive at the hospital and then pay the remainder before they discharge you. They accept Credit/debit cards and cash.

Because of course they do. Reading this makes me understand why the administration of Hospital Angeles is willing to let Drs. Siller and Garcia do their thing there. It’s a profit center. The hospital makes money if everything goes smoothly, and it makes even more money if patients don’t do so well and required prolonged hospitalizations. For instance, as I mentioned last week, Annabelle Nguyen is in a coma, her DIPG having recurred. It’s costing the family $2,500 a day, and her parents can’t get her home to Australia because a medical flight would cost $250,000. As of this weekend, she was still there; today represents 60 days in a coma. I can’t imagine a more horrible dilemma for a family to be in, trapped thousands of miles from home and racking up huge medical bills because it costs too much to bring your child home.

No conventional therapy preferred

I’ve often said that one characteristic of a quack is that the quack will blame conventional therapy, such as chemotherapy and radiation, that the patient might have undergone before coming to him for any failure of his nostrums to cure the patient. In that very same Facebook post listing the costs and providing information for families, we learn this:

The treatment is Intra-arterial Chemotherapy Infusion Treatments and immunotherapy. They do immunotherapy but the child has to be totally off any steroids for several months.

As I’ve discussed many times before when discussing Stanislaw Burzynski, the reason steroids are administered to brain cancer patients is to cut down on inflammation and swelling provoked by the tumor. Because the skull is a non-expandable space, any swelling will result in increased pressure, which will damage brain tissue. I listed another reason above why these children with DIPG treated through Clínica 0-19 are likely to be in better shape physiologically than the average DIPG patient. Here’s another. They have to be off steroids, not just briefly but for several months. Any child with DIPG who can be off steroids for several months had a tumor that responded very well to radiation therapy and remained dormant for quite some time and/or is a more indolent, slow-growing variety of DIPG.

Speaking of conventional therapy, here’s another disturbing aspect of IDOI’s protocol that I didn’t mention last week:

It is preferred that the child has NOT had radiation before IA treatment, but is not required. They will treat children who have had radiation and have even treated children who have had it twice. After treatment – The child may experience headaches, sickness, fever, backache, groin pain, and loss of appetite immediately after treatment.

On the IDOI FAQ:

What are your thoughts on radiation?

Usually we do not indicate radiotherapy in our patients, when we come to need it (very occasionally), we indicate it in a particular way in an attempt of being the least aggressive with healthy brain tissues around the tumor. Can we get treatment without doing radiation?

Yes, that would be ideal. For us, radiation is the last choice.

Most patients who end up at Clínica 0-19 appear to have already had radiation therapy and then shown evidence of recurrence, the recurrence being what drives parents to seek out alternatives. However, telling parents that they should forego radiation therapy in favor of an unproven treatment, saving it for absolutely the last resort while Drs. Siller and Garcia subject their child to their unproven, invasive, and potentially toxic therapy, is the height of irresponsibility.

The more I find out, the more horrified I am

When I first discovered Clínica 0-19 and IDOI, I was willing to give Drs. Siller and Garcia a little bit of the benefit of the doubt. Sure, I was very suspicious based on first impressions that what they were doing was, in essence, quackery, their boasting of using only FDA-approved medications notwithstanding. The more I find out, the more convinced I become that my initial impression was probably correct. All the red flags are there: a highly secretive clinic whose doctors won’t publish their protocol or even survival statistics; charging families enormous sums of money, cash on the barrelhead; no science to support their claims; and a network of patients and supporters who both sell the clinic’s treatment through their testimonials and attack critics. That is Burzynski’s model. It is also the Hallwang Clinic’s model. It is Clínica 0-19’s model.

As a result, patients and families suffer, as we will see in the next installment, which I promise to write before the end of July.

The complete series