Why a case report being circulated by advocates doesn't show that the ketogenic diet combats cancer

It's October again, which is Breast Cancer Awareness Month. As someone who takes care of breast cancer patients, I have a love-hate relationship with October. On the good side, I like seeing positive messages about what's going on in breast cancer research, advocacy, and clinical treatment. On the other hand, the quacks come out. I also see a lot of bad breast cancer studies. You might think that I'd like that too because it provides blog fodder. I could actually do without that, but in this case I happened to come across a "study" that illustrates why I detest how those promoting unproven treatments prey upon the misconceptions and lack of knowledge the average person has about breast cancer. So it was when I encountered this on Twitter:

1) Study showing aggressive metastasized #breastcancer defeated with a #ketogenicdiet #lchf https://t.co/oWx7xngV1w

— Low Carb High Fat (@lowcarblonglife) October 3, 2017

With this followup:

Ketogenic diet was part of the Press Pulse strategy used as a complement to the normally ineffective chemotherapy.

— Low Carb High Fat (@lowcarblonglife) October 3, 2017

With this followup:

Ketogenic diet was part of the Press Pulse strategy used as a complement to the normally ineffective chemotherapy.

— Low Carb High Fat (@lowcarblonglife) October 3, 2017

I've written about the ketogenic diet before, specifically about how it is more hype than science right now. I just realized reading my previous post that it's been three years since I've done an in-depth post on ketogenic diets. Who knows? Maybe someone's published something more recently that might make me change my mind. However, if that's the case, it's certainly not a study like the one Tweeted above, co-authored by Thomas Seyfried, the guru of ketogenic diets whom we've met before.

As you might recall from the last time I discussed him, Dr. Seyfried is a professor of biology at Boston College, who’s pretty well published. He’s also working in a field that has gained much more respectability over the last five to ten years, namely cancer metabolism, mainly thanks to a rediscovery of what Otto Warburg discovered over 80 years ago. What Warburg discovered was that many tumors rely on glycolysis for their energy even in environments with adequate oxygen for oxidative phosphorylation, which generates the bulk of the chemical energy used by cells. I first described this phenomenon in more detail in a post I wrote seven years ago about a drug that looks as though its anticancer properties come from its ability to reverse the Warburg effect.

Unfortunately, Dr. Seyfried has also gone a bit off the deep end pursuing this idea, and the paper Tweeted above by him and co-investigators, as you will see. The paper is Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer. Sounds pretty serious, right? Unfortunately, this is just a case report, and it was carried out at a rather dubious clinic in Istanbul called the ChemoThermia Oncology Center, which specializes in combining chemotherapy with hyperthermia, which in and of itself is not quackery, albeit it is only potentially useful for a handful of cancers, where it's used in the form of hyperthermic intraperitoneal chemotherapy. However, in this case, what is being used is something called "metabolically supported chemotherapy" (MSCT), which was combined with a ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen (HBOT). So right there, just reading the abstract, my skeptical antennae started twitching. It sounds as though everything but the kitchen sink, but it's worse than that. Check out this passage:

In practice, MSCT initiates with a 12-hour fast, the application of pharmacological doses of regular insulin, and the development of mild hypoglycemia prior to the administration of chemotherapy. As was previously demonstrated in a case report of rectal cancer and a case series in pancreatic cancer, MSCT may enhance the cytotoxic effects of chemotherapy [4-5].

What they're talking about here is insulin potentiation therapy (IPT), which is not just unproven, but it's potentially dangerous quackery. The clinic itself touts case presentations that aren't even really case presentations, just pictures of shrinking tumors. I note that regular, run-of-the-mill standard-of-care chemotherapy can frequently shrink tumors, even metastatic tumors. What has to be shown is that this concocted regimen put together by the ChemoThermia Oncology Center actually does better than conventional chemotherapy. There is no evidence of that I can find anywhere on the website, but, a lot like the Rigvir website, there are testimonials and a crappy retrospective study.

But what about the case report itself? Well, let's take a look:

An overweight 29-year-old woman with a body mass index (BMI) of 28.1 presented with a lump in her left breast that was detected during a physical examination in December 2015. The patient was admitted to Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey in August 2016, with interval enlargement of the tumor. Magnetic resonance imaging revealed a 75 mm x 75 mm x 65 mm left breast mass (Breast Imaging Reporting and Data System Category 5) with irregular borders. Multiple lymphadenomegaly was seen in the left axilla with the largest being 27 mm x 20 mm. A Tru-Cut biopsy led to a diagnosis of a nuclear grade 2 invasive ductal carcinoma that was negative for ER, PgR, and HER2 receptors (Figures (Figures--44).

This is what we in the biz call "triple negative breast cancer" (TNBC). It's a subtype of breast cancer that tends to be more aggressive, like cancers with amplified HER2 receptor. The difference is that HER2(+) breast cancer can be treated with targeted drugs like Herceptin and Perjeta, along with chemotherapy, to great effect. Estrogen receptor-positive cancers can be treated with hormonal therapy, specifically drugs that block the action of estrogen. For TNBC there are not as of yet any approved targeted drugs. That just leaves cytotoxic chemotherapy. Also, note the extreme young age of the patient. Breast cancer is relatively rare under the age of 30. (I've only seen a handful of such patients over my 18 year career.) Unfortunately, breast cancer tends to be more aggressive in young women like this.

To translate the above: This is a 29-year-old woman with a large, locally advanced breast cancer with positive axillary lymph nodes (under the arm). That makes her at least stage 3 right off the bat. Unfortunately, it was worse than that. It was stage 4:

The patient was admitted to ChemoThermia Oncology Center, Istanbul, Turkey on October 1, 2016 and was evaluated using whole body (18F)-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT). The PET-CT scan revealed a 77 mm x 55 mm primary tumor in her left breast (maximum standard update value [SUVmax]: 22.65), multiple left pectoral and axillary lymph nodes (SUVmax: 11.44), multiple widespread liver masses (SUVmax: 30.34), and an upper left nodular abdominal lesion (SUVmax: 5.94) (Figure (Figure5,5, Video Video1).1). The patient was diagnosed with stage IV (T4N3M1) triple-negative invasive ductal carcinoma of the breast.

So, in addition to her local disease, she also had liver metastases and soem sort of upper abdominal mass. Neither of these were reported to have been biopsied, but, given their lighting up on PET scan, it's reasonable to conclude that they are metastases. However, here in the states, most oncologists would have biopsied one of the liver lesions to prove it.

So here's what happened next:

An MSCT protocol designed for the patient consisted of docetaxel (30 mg/m²), doxorubicin (20 mg/m²), and cyclophosphamide (250 mg/m²). This drug combination was administered following a 12-hour fast and the introduction of 5 to 10 units of regular insulin (Humulin R). Chemotherapy delivery was initiated at blood glucose levels of 50 to 60 mg/dL. With the patient’s written and informed consent, this therapy was delivered on the first and eighth day of a 21-day cycle for a total of four months. Insulin delivery and chemotherapy infusions were delivered after assessing blood glucose levels upon arrival at the clinic, and the insulin dosage was sufficient to lower her blood glucose to approximately 50 mg/dL prior to delivery of the chemotherapy drugs.

In addition to MSCT, the patient was encouraged to consume a KD. She received education regarding the diet restrictions and given food lists as noted in Table 1.

I'm a bit confused here. The standard of care is to give doxorubicin and cyclophosphamide together for a certain number of cycles, a combination referred to as AC (A=Adriamycin, the trade name of doxorubicin; C=Cytoxan, the trade name of cyclophosphamide). This is then followed by a drug related to Taxol, such as paclitaxel or docetaxel, administered as a single agent. The abbreviation of the whole regiment is thus ACT or AC, followed by T. I'm assuming that this is what this patient received, but the way it's written above sounds like they were given all together, which is not standard of care and would be expected to produce more toxicity. Certainly not standard of care is the IPT, nor is the KD. Nor is this:

The patient also received local HT and HBOT after each MSCT session. The OncoTherm EHY-3010 HT device (OncoTherm, Troisdorf, Germany) was used to gradually increase her body temperature to 45°C for each hyperthermia session (12 sessions, 60 minutes each) according to the manufacturer’s specifications. A mobile electrode measuring 40 cm x 50 cm was positioned on the thorax and abdomen that fully involved both the primary lesion and the liver metastasis. The Quamvis 320 hyperbaric oxygen chamber (OxyHealth, California, US) was used to produce an operating pressure of 1.5 atmospheres absolute (ATA; 12 sessions, 60 minutes each). The patient tolerated these combined therapies well with no evidence of toxicity or adverse events.

This is hyperthermia higher than is usually used, which is usually done at 41°-42°C They're doing 45°C, which is 113°F. That's at the very highest end of what is used.

At the end of her therapy, on February 20, 2017, the patient underwent repeat imaging, which showed nothing lighting up on PET scan other than the kidneys, which normally light up. Then in April, she underwent a modified radical mastectomy, which showed what we call a complete pathologic response (cPR) to chemotherapy. What that means is that, upon pathological examination of the resected breast and lymph nodes, no viable tumor cells were found. So this is as good a result as can be expected.

Now, our friend Tweeting above said, "normally ineffective chemotherapy." That is, of course, nonsense. If there's one thing about TNBC, it's that it's usually exquisitely sensitive to chemotherapy—at least at first. It's not uncommon to observe dramatic tumor shrinkage due to chemotherapy. What makes TNBC such a bad actor is that it tends to recur rapidly and develop resistance to chemotherapy. So, basically, it is not at all surprising that this woman had a dramatic response to chemotherapy, and there's no way of knowing whether the ketogenic diet contributed to her excellent response.

Yet, as we see above, this case report is being represented as a "miracle cure":

?Tks! I'm interested to know, but details like that don't seem to matter to #KetoBrigade for hailing it as near miracle cure for TNBC. Ugh. pic.twitter.com/HLEU5wXWf9

— Quidama (@IamBreastCancer) October 4, 2017

The authors also seem unduly impressed:

Given the poor prognosis and adverse effects, women with advanced TNBC may be counseled to forego conventional chemotherapy. This single case study presents evidence of a complete clinical, radiological, and pathological response following a six-month treatment period using a combination of MSCT and a novel metabolic therapy in a patient with stage IV TNBC. Given this patient’s remarkable favorable outcomes, further research and randomized clinical trials exploring add-on therapies (such as KD, HT, and HBOT) that may enhance the efficacy of traditional cancer treatments by exploiting the metabolic weaknesses in cancer cells are warranted, especially for patients with poor prognosis of high grade and/or late-stage cancer that is not expected to respond to treatment. Furthermore, this patient did not experience the adverse effects that are commonly associated with the current standard of care and this improved quality of life should also be considered when designing research that compares outcomes of MSCT, KD, HT, and HBOT to traditional treatment. In conclusion, this combined metabolic approach appears effective in treating advanced TNBC, given this patient’s complete response with a good quality of life.

Now, there is one thing that is interesting here. The doses of chemotherapy used were considerably lower than what is usually used, with doses decreased by at least half or more. Does this mean anything? Who knows? cPR rates for TNBC have been reported to range from 20-35%. It could mean the regimen made the chemotherapy more effective, or it could mean that this woman just happened to have a particularly chemosensitive tumor. Even if we take this case report at face value and accepted that chemotherapy efficacy had been improved, there's no way of knowing what did it. Was it the ketogenic diet? Was it the hyperthermia? Was it the IPT? (Actually, we know it almost certainly wasn't the IPT based on what is already known; certainly no studies of long term survival have been published.)

In any case, what we have here is a patient with stage 4 TNBC who underwent chemotherapy and surgery, showed a dramatic response, and then underwent surgery. She had a complete radiological response of her metastases (they were no longer detectable on imaging studies) and a complete pathologic response on her surgical specimen. She was alive six months after she started treatment. Assuming she's alive now, she's been alive a little more than a year with her diagnosis. That's nowhere outside the range of survival for stage 4 breast cancer, which has a roughly 20% five year survival. Indeed, extrapolating from what we know about neoadjuvant chemotherapy in TNBC (chemotherapy given before surgery), where pCR correlates with prolonged survival, it's not unreasonable to predict that this patient will do significantly better than the average patient with stage 4 TNBC. That this patient is alive now tells us nothing about whether the treatment used will prolong her life, and it certainly tells us nothing about whether everything larded onto the chemotherapy had anything to do whatsoever with her outcome. If anything, her excellent response is probably indicative of more favorable biology of her tumor than anything else.

Unfortunately, because most people don't know a lot about breast cancer or chemotherapy, this case report will sound very compelling to them.