One of many tough issues about science-based medication is figuring out what’s and isn’t quackery. Whereas it’s fairly apparent that modalities resembling homeopathy, acupuncture, reflexology, craniosacral remedy, Hulda Clark’s “zapper,” the Gerson remedy and Gonzalez protocol for most cancers, and reiki (to not point out each different “power therapeutic” remedy) are the rankest quackery, there are many remedies which are tougher to categorise. A lot of the time, these remedies that seemingly fall right into a “grey space” are remedies which have proven promise in animals however have by no means been examined rigorously in people or are based mostly on scientific ideas that sound cheap however, once more, have by no means been examined rigorously in people. (Are you sensing a sample right here but?) Typically these therapies are promoted by true believers whose enthusiasm vastly outstrips the proof base for his or her most well-liked remedy. Recently, I’ve been seeing simply such a remedy being promoted across the traditional social media sources, resembling Fb, Twitter, and the like. I’ve been that means to put in writing about it for a bit, however, as is so usually the case with my Dug the Canine nature—squirrel!—different subjects caught my consideration.
I’m referring to a weight loss plan referred to as the ketogenic weight loss plan, and an article that’s been making the rounds since final week entitled “Ketogenic weight loss plan beats chemo for nearly all cancers, says Dr. Thomas Seyfried.” After all, once I see a declare resembling that, my first response is, “Present me the proof.” My second response is, “Who is that this man?” Nicely, Dr. Seyfried is a professor of biology at Boston School, who’s fairly nicely revealed. He’s additionally working in a area that has gained new respectability during the last 5 to 10 years, particularly most cancers metabolism, primarily due to a rediscovery of what Otto Warburg found over 80 years in the past. What Warburg found was that many tumors depend on glycolysis for his or her power even in environments with sufficient oxygen for oxidative phosphorylation, which generates the majority of the chemical power utilized by cells. I described this phenomenon in additional element in a publish I did 4 years in the past a few drug that appears as if its anticancer properties come from its capability to reverse the Warburg impact.
What to not do in order for you your speculation to be taken significantly
So on the floor, Dr. Seyfried’s argument that most cancers is primarily a metabolic illness (an argument I’ll take a look at in additional depth shortly) is nicely inside the bounds of present oncologic science. Certainly, a couple of years in the past it was all the craze, and I bear in mind attending a number of classes and lectures on the Warburg impact and most cancers on the AACR conferences three or 4 years in the past, though, oddly sufficient, I don’t recall as many the final couple of years. In any occasion, if that’s all I checked out, I in all probability would have shrugged my shoulders and moved on, as in, “Nothing to see right here.” However there are fairly a couple of pink flags. The primary pink flag is a declare {that a} ketogenic weight loss plan can deal with most cancers higher than chemotherapy. The second, even larger, pink flag is on Dr. Seyfried’s Boston School internet web page:
As well as, Dr. Seyfried has labored with famous different well being advocate Dr. Mercola to supply a thought-provoking dialogue on the advantages of a ketogenic weight loss plan. Dr. Mercola offers an intensive synopsis of the discuss on his web site, and likewise contains the unique audio recording of their dialog.
Über-quack Dr. Mercola? Oh, expensive. His evident delight at having been interviewed by Dr. Mercola doesn’t replicate nicely on Dr. Seyfried’s vital pondering abilities and information of medication. Dr. Mercola sells quackery. He has promoted antivaccine views, breast most cancers pseudoscience, and the rankest most cancers quackery, resembling that of Tullio Simoncini, who believes that every one most cancers is a fungus and that baking soda is the best way to deal with it, and the Gerson remedy, which includes huge doses of dietary supplements and, after all, twice-a-day espresso enemas. Significantly, this isn’t the kind of individual a authentic scientist needs to affiliate himself with—ever—if he needs to be taken significantly. I can see a naive researcher making a mistake and, not realizing who Dr. Mercola is, agreeing to an interview, however that’s the kind of factor {that a} respected scientist would do his greatest to disavow and distance himself from.
Neither is the American School for Development in Medication (ACAM), which payments itself because the “voice of integrative medication,” the place he’s given a significant discuss, the kind of group a authentic scientist needs to affiliate himself with if he needs to be taken significantly. Don’t consider me? Simply peruse the ACAM web site, the place you will see that numerous chelation remedy, together with a program to “certify” in chelation remedy and detoxing, in addition to different quackery. There’s purpose that ACAM has appeared in many SBM posts all through the years, and never in a positive gentle. I emphasize once more, this isn’t a company with which a scientist who needs to be taken significantly by oncologists associates himself.
Additionally, if a scientist needs to be taken significantly, he shouldn’t say issues like this:
The low-carb, high-fat ketogenic weight loss plan can exchange chemotherapy and radiation for even the deadliest of cancers, mentioned Dr. Thomas Seyfried, a number one most cancers researcher and professor at Boston School.
In an unique interview, Dr. Seyfried mentioned why the ketogenic weight loss plan has not been embraced by the medical neighborhood to deal with most cancers regardless of its confirmed monitor report each clinically and anecdotally.
“The rationale why the ketogenic weight loss plan just isn’t being prescribed to deal with most cancers is solely economical,” mentioned Dr. Seyfried, creator of Most cancers as a Metabolic Illness. “Most cancers is large enterprise. There are extra folks making a residing off most cancers than there are dying of it.”
And don’t affiliate your self with Ralph Moss, the primary promoter of laetrile quackery and make simply refuted claims such because the declare that “chemo and radiation don’t remedy most cancers or prolong life, though most cancers physicians usually make this declare” and that radiation “usually does extra hurt than good to the affected person.” Given that every one Dr. Seyfried has is a few case research as medical assist for his remedy (see beneath) and I can produce reams of research over practically 50 years demonstrating that chemotherapy can remedy particular cancers and lengthen life when used appropriately, the “2% gambit” however, it’s not a profitable proposition, and it positive doesn’t assist your credibility to make use of the language of most cancers quacks to advertise your concept.
So, what, precisely is Dr. Seyfried’s speculation?
Most cancers as a metabolic illness
Crimson flags or no pink flags, it’s, after all, attainable that Dr. Seyfried is on to one thing and has let his enthusiasm overwhelm his judgment with respect to whom he associates with and the kinds of statements he makes, lots of which sound as if they might have come from Stanislaw Burzynski, Ralph Moss, or Joe Mercola. In truth, he isn’t completely fallacious, however he isn’t completely proper, both. As is typical of somebody with no medical background, particularly an oncology background, he’s, principally, placing the cart earlier than the horse, as you will notice.
In his discuss, Dr. Seyfried begins with what he refers to as a “provocative query”: Is most cancers a genetic or metabolic illness? Truly, whether or not he realizes it or not, his query just isn’t fairly as provocative as he thinks it’s, neither is the reply anyplace close to as clear-cut as he thinks it’s or as he characterizes oncologists and most cancers researchers as pondering it’s. I’ll let you know what I believe the reply to the query is after I’ve mentioned Dr. Seyfried’s speculation. Within the meantime, not surprisingly, his reply is that most cancers is a metabolic illness, whereas everybody else’s reply—in accordance with him, no less than—is that it’s a genetic illness, making him the courageous maverick physician, who says issues like:
The present view now, with none query, is that most cancers is a genetic illness. When you go on the Nationwide Most cancers Institute web site otherwise you learn any of the key articles revealed in Nature and Science, usually the articles will begin with, “Most cancers is a genetic illness.” I believe that this has change into dogma.
Besides that it actually isn’t, no less than not anymore. When you do a Pubmed search on “focusing on most cancers metabolism,” which is what Dr. Seyfried is speaking about, you’ll discover over 22,000 articles, with over 3,000 in 2013 alone, with a sharply growing curve since 2000 that solely now seems to be leveling off. A search on “most cancers metabolism” brings up 369,000 references, with 28,000 in 2013 alone. Most cancers metabolism is an extremely vital subject in most cancers analysis and has been for a number of years now, and discovering technique of focusing on the widespread metabolic abnormalities exhibited by most cancers cells is at present a sizzling space of analysis. From my perspective, Dr. Seyfried is exaggerating how hostile the most cancers analysis neighborhood is in the direction of metabolism as an vital, probably vital, driver of most cancers, though, to be honest, one distinguished most cancers researcher, Robert Weinberg, has been very skeptical. To me, Seyfried simply seems sad that genetics is at present thought—for good causes, I’d add—to be the first driver of most cancers. Notice that I deliberately used such phrasing, as a result of Dr. Seyfried, in my readings, seems all too usually to talk of “most cancers” as if it had been a monolithic single illness. As I’ve identified many instances earlier than, it’s not. Certainly, solely roughly 60-90% of cancers reveal the Warburg impact.
There are three parts to glucose metabolism: glycolysis, which feeds the Krebs citric acid cycle, which in flip feeds oxidative phosphorylation. I present them beneath in simplified illustrations:
The problem with the Warburg impact is that it results in a shift in metabolism that favors glycolysis. Because of this shift, tumor cells have a tendency to make use of much more glucose than regular cells as a result of glycolysis is far much less environment friendly at changing glucose into ATP molecules used for mobile power than oxidative phosphorylation. One purpose that that is thought to supply a development benefit to most cancers cells is as a result of oxidative phosphorylation requires oxygen whereas glycolysis doesn’t and cancers regularly outgrow their blood provide such that they usually reside and develop in tissue areas the place there may be not a lot oxygen. In any case, the avidity of most cancers cells for glucose has been identified a very long time and is the idea for positron emission tomography (PET) scanning, the place a radiolabeled by-product of glucose is essentially the most generally used tracer for precisely that purpose: Tumor cells take it up way more avidly than do regular cells, resulting in ugly black blobs (old style PET scans alone) or fairly shiny blobs (PET-CT) the place there are tumor plenty within the scans.
The concept behind ketogenic diets could be very easy. If glucose is the first gas for most cancers, then decrease carbohydrate consumption and exchange carbohydrates with different sources of gas, resembling fat, in an effort to push the physique’s metabolism into ketosis. It really seems that ketogenic diets are in all probability helpful within the remedy of intractable epileptic seizures in youngsters. Sadly, their mechanism of motion in stopping seizures is unclear, though 4 potential mechanisms, together with carbohydrate discount, activation of ATP-sensitive potassium channels by mitochondrial metabolism, inhibition of the mammalian goal of rapamycin (mTOR) pathway, or inhibition of glutamatergic synaptic transmission (glutamate as a neurotransmitter), have been proposed. Curiously, the mTOR pathway is an vital signaling pathway in lots of cancers that {couples} power and nutrient abundance to the execution of cell development and division, owing to the flexibility of TOR protein kinase to concurrently sense power, vitamins and stress and development components. It’s a generally overactive signaling pathway in most cancers.
It’s additionally fascinating that the cancers used to provide the fundamental science cited by Dr. Seyfried are just about all mind cancers and that just about all of the proof comes from rodent tumor fashions. For one factor, if there’s a tumor sort that displays the Warburg impact and a excessive diploma of metabolic derangement, it’s mind tumors. It’s no coincidence that dichloroacetate was first examined in mind tumors. On this research, VM/Dk mice had been used, and a mouse histiocytoma cell line resembling human glioblastoma multiforme with macrophage/microglial properties derived from that very same mouse pressure (VM-M3) was implanted subcutaneously. This cell line has the property of metastasizing rapidly and extensively when implanted beneath the pores and skin and allowed to develop, which really makes it not very very similar to mind tumors, which seldom metastasize and often kill via native invasion and taking over growing quantity within the closed house of the cranium, one thing the mind most positively doesn’t like. The outcomes confirmed {that a} ketogenic weight loss plan elevated imply survival time by over 56%, whereas a mix of a ketogenic weight loss plan and hyperbaric oxygen remedy (HBOT) elevated survival time 78%. The result’s fascinating, however it’s a mouse tumor mannequin, not a human tumor mannequin, and that makes its applicability to people tenuous, notably given the character of the murine tumor, however in all probability price investigating additional.
One other mouse research cited by Seyfried is one during which dietary restriction was reported to advertise vessel maturation in a mouse astrocytoma mannequin. On condition that tumor angiogenesis is one among my scientific pursuits and I’ve a good variety of publications on the subject, I used to be . Sadly, I ended up being disillusioned. This was one other syngeneic mannequin (i.e., a mouse tumor implanted in mice of the identical pressure from which the tumor was remoted as a cell line, just like the one mentioned above). Though it confirmed elevated tumor vessel maturation (which is one mechanism by which inhibitors of angiogenesis work), I wasn’t fairly satisfied, as a result of there was a definite lack of quantification of the phenomenon, and the microscopy seems to not have been blinded, one thing that’s vital to keep away from unconscious bias within the outcomes. It’s not shocking that this consequence, which, if extra convincing proof had been obtained, might simply have appeared in Most cancers Analysis, was revealed in a low tier journal. It’s an OK research, however not improbable. Actually it didn’t lead me to smacking myself in brow and saying, “After all!”
All through his talks, each right here and elsewhere, Dr. Seyfried presents mouse research which are fascinating and suggestive that there is likely to be one thing to this entire ketogenic weight loss plan factor, no less than in mind tumors, resembling this one. Nevertheless, that is what we within the oncology biz would name fairly preliminary knowledge, worthy of additional investigation however not supporting the grandiose claims that Dr. Seyfried makes.
We’d like extra beef. We’d like medical research. Sadly, they’re in brief provide.
Medical proof for ketogenic diets as a most cancers remedy
It’s not as if Dr. Seyfried doesn’t cite medical proof. It’s simply that the proof is so darned skinny and unconvincing to this point. For example, on this discuss, the primary research he presents is a very small case collection (two sufferers, really) carried out in 1995 during which two ladies with inoperable astrocytomas had been positioned on a ketogenic weight loss plan in an effort to “decide if a ketogenic state would lower glucose availability to sure tumors, thereby doubtlessly impairing tumor metabolism with out adversely affecting the affected person’s general dietary standing.” Curiously (to me, no less than) these case experiences got here from College Hospitals of Cleveland, the place I did my basic surgical procedure residency. In truth, I used to be nonetheless there in 1995. Sadly, I don’t have entry to the journal again to 1995; so I’m caught with simply the summary. Nevertheless, the summary is fairly clear:
Inside 7 days of initiating the ketogenic weight loss plan, blood glucose ranges declined to low-normal ranges and blood ketones had been elevated twenty to thirty fold. Outcomes of PET scans indicated a 21.8% common lower in glucose uptake on the tumor web site in each topics. One affected person exhibited vital medical enhancements in temper and new talent improvement throughout the research. She continued the ketogenic weight loss plan for an extra twelve months, remaining freed from illness development.
One notes that the affected person who didn’t survive 12 months wasn’t a lot talked about; so I assume she didn’t reveal any medical enchancment. In any case, this research doesn’t actually present something, aside from {that a} ketogenic weight loss plan would possibly lower glucose uptake in some mind tumors. It’s like a Burzynski case report, during which we don’t know whether or not the affected person did higher than anticipated due to the intervention or as a result of she had much less aggressive illness.
The following case report is from 2010. It describes the case of a 65-year-old girl who introduced with progressive reminiscence loss, power complications, nausea, and a proper hemisphere multi-centric tumor seen with magnetic resonance imaging (MRI). Following incomplete surgical resection, the affected person was recognized with glioblastoma multiforme (GBM). Now right here’s the kicker: The affected person underwent customary remedy plus the ketogenic weight loss plan. A day after her surgical procedure, she underwent a two-day quick, adopted by a 3 day quick starting every week after surgical procedure, adopted by a restricted ketogenic weight loss plan (solely 600 Cal/day). Three weeks after her surgical procedure (and two weeks after beginning the ketogenic weight loss plan) she started customary of care remedy, concomitant radiation plus chemotherapy (temozolomide), “in accordance with customary procedures,” which lasted six weeks. The affected person additionally had a gene mutation in her tumor that produces elevated sensitivity to temozolomide. The conclusion? Thankfully for the affected person, she had what seems to have been a whole response, after which she went on a much less restrictive ketogenic weight loss plan. Sadly, the affected person recurred eight months later. By that time, the affected person was off of the ketogenic weight loss plan. The authors’ conclusion? As a result of it was “unlikely” that the tumor would have responded this nicely on customary remedy alone, it should have been including the ketogenic weight loss plan that accomplished it. Worse, within the discuss, Dr. Seyfried strongly implies that the tumor recurred as a result of she had gone off the ketogenic weight loss plan two and a half months earlier than her recurrence.
Irritatingly, throughout the identical discuss, Dr. Seyfried refers to having accomplished a “biopsy” on the GBM when the case report clearly says that the affected person underwent a partial excision of the temporal pole with incomplete debulking of the tumor, which is a special factor. When a surgeon tries to debulk a tumor, he’s attempting to take away as a lot of it as attainable. When a surgeon biopsies a tumor, he’s attempting solely to get sufficient tissue to make a analysis. He additionally heaps scorn on the hospital for insisting that the affected person endure customary of care remedy, clearly demonstrating that he has no understanding of medical trial ethics. What most probably occurred with this affected person is that the debulking was vital, and the remaining tumor was sufficiently small to be eradicated by the mixed chemotherapy and radiation remedy—no less than to the purpose of now not being detectable on PET scan. Additionally, simply because the weight loss plan seems to have decreased glucose uptake by the tumor doesn’t imply that the tumor was dying. In truth, it might need even made the PET scan much less delicate to no matter remaining viable tumor cells would possibly nonetheless have been round, a chance that I don’t see Dr. Seyfried as having thought of.
There are different research, however little or nothing in the best way of randomized medical trials. For example, a latest retrospective research of 53 sufferers, of whom solely six adopted a ketogenic weight loss plan whereas being handled for GBM, concluded that the weight loss plan was protected, however no suggestion of efficacy was famous. Extra lately, a German group examined the impact of a ketogenic weight loss plan on 16 sufferers with superior most cancers of assorted varieties who had exhausted all therapeutic choices. The remedy didn’t end in any critical unwanted side effects, though topics discovered it very tough to take care of the weight loss plan, notably within the context of household life. Solely 5 had been in a position to full the three month remedy interval, and it was reported that these 5 didn’t have development whereas on the weight loss plan. Of the remaining 11, two died early, one was unable to tolerate the weight loss plan and dropped out in a short time, two dropped out for private causes, one couldn’t proceed the weight loss plan for greater than a month and three had illness development inside lower than 2 months of beginning the weight loss plan and one dropped out to renew chemotherapy. As a complete, this research was well-nigh uninterpretable as a result of completely different sorts of most cancers, aside from to conclude that lower than 50% of sufferers with superior most cancers might adhere to the weight loss plan, and that those that might usually had no vital unwanted side effects. After all, it’s unclear whether or not the weight loss plan helped the 5 who might adhere to it or whether or not those that adhered to it might achieve this as a result of they’d extra indolent, much less aggressive illness.
None of this stops Dr. Seyfried from concluding:
- Preclinical and case report research indicated that the restricted ketogenic weight loss plan (R-KD) may be an efficient “metabolic remedy” for managing malignant mind most cancers in youngsters and adults.
- The therapeutic results of the R-KD towards mind most cancers may be enhanced when mixed with medicine or HBOT that additionally goal power metabolism.
Uh, no. Not precisely. Preclinical experiments are intriguing however pretty restricted in applicability, and the case experiences reveal nothing of the type. There’s extra to Dr. Seyfried’s speculation, for instance, his concept that metastatic most cancers comes about due to alterations in glutamine metabolism, however sadly he seems to misconceive the genetics of metastasis when he bases a part of his conclusion on observations that metastatic cancers usually have the identical genetic derangements as the first tumor. It’s been a longstanding query whether or not clones of tumor cells possess the flexibility to metastasize as an intrinsic a part of the method of changing into most cancers cells or whether or not they purchase it later. On condition that evolution is a significant power driving most cancers cells to change into extra invasive and that tumors are very heterogeneous, stuffed with numerous completely different clones with completely different units of genetic mutations, Dr. Seyfried’s speculation is at greatest simplistic. Additionally disappointingly, the proof for any weight loss plan as a remedy for most cancers is weak at greatest.
Placing the cart earlier than the horse
Clearly, ketogenic diets will not be prepared for prime time as a remedy for most cancers, both alone or together with typical remedy. Sadly, that hasn’t stopped it from being touted by all method of other most cancers practitioners (i.e., quacks) and others as a most cancers remedy that “they” don’t need you to find out about or saying issues like, “…it’s nothing in need of medical malpractice and negligence to fail to combine the sort of dietary technique right into a affected person’s most cancers remedy plan,” as Joe Mercola did. Dr. Seyfried himself has contributed to the hyperbole fairly a bit as nicely. For instance:
These research are all together with both radiation or chemotherapy. My desire is to start out metabolic remedy with GBM (glioblastoma multiforme). It is a devastating sort of mind most cancers. Metabolic remedy with a restricted KD might be accomplished with a couple of tumors the place you understand the traditional customary of care doesn’t work in any respect. You’d select these sorts of sufferers and do a medical trial based mostly on historic controls and see what the end result could be and see for those who might get some degree of survival that may match or be higher than the traditional customary of care.
Common readers of SBM ought to know the issue with this kind of method. No IRB price its salt would approve such a trial as a result of it might be ethically doubtful, however, even worse, it might be ethically doubtful and it wouldn’t actually inform us something until these few sufferers both had near-miraculous responses or died in a short time. Anything would merely inform us that the weight loss plan might be doing no hurt. Extra numbers could be wanted, notably if the comparability is to historic controls, to get even an inkling of whether or not there is likely to be profit. In that case, you would possibly as nicely do a correct section I/II medical trial, which is what is occurring. For example:
In different phrases, medical knowledge must be rolling in pretty quickly, and that’s factor. Within the meantime Dr. Seyfried and different advocates who so passionately consider that ketogenic diets will vastly assist sufferers with mind most cancers do nobody any favors by claiming unequivocally that most cancers is a metabolic illness and saying that ketogenic diets are extra useful than chemotherapy for sufferers with mind tumors.
This brings me again to the query of whether or not most cancers is a metabolic illness or a genetic illness, the reply to which I promised early on. The doubtless reply? It’s each! Certainly, a “hen or the egg” argument continues about whether or not it’s the metabolic abnormalities that trigger the mutations noticed in most cancers cells or whether or not it’s the mutations that produce the metabolic abnormalities. More than likely, it’s slightly of each, the precise proportion of which relying upon the tumor cell, that mix in an unholy synergistic circle to drive most cancers cells to be increasingly more irregular and aggressive. Furthermore, most cancers is about way over simply the genomics or the metabolism of most cancers cells. It’s additionally the immune system and the tumor microenvironment (the cells and connective tissue during which tumors come up and develop). As I’ve mentioned time and time and time once more, most cancers is difficult, actual difficult. The relative contributions of genetic mutations, metabolic derangements, immune cell dysfunction, and influences of the microenvironment are more likely to differ relying upon the kind of tumor and, as a consequence, require completely different remedies. In the long run, as with many hyped most cancers cures, the ketogenic weight loss plan is likely to be useful for some tumors and virtually actually gained’t be useful for others. Dr. Seyfried is likely to be on to one thing, however he’s gone a bit off the deep finish in apparently pondering that he’s discovered one thing about most cancers that nobody else takes significantly—or has even considered earlier than.
