Fact-Checking the Works of KD on Cancer

Introduction

Talks among peers and celebrities have been filled with the wonders of the Ketogenic Diet (KD) as the trendiest way to fast weight loss. This keto diet hype has been fueled by social media and so it pushes a challenge to medical professionals, most especially Registered Nutritionist-Dietitians, to educate people that weight loss takes a steady pace, and the true goal should be centered on a healthy lifestyle. With the word “fast” as the first red flag, jumping into a diet without proper medical guidance is the second red flag. 

The Roots of Ketogenic Diet

The ketogenic diet program was not developed for weight loss; it was created for managing epileptic seizures.¹ In 1924, when anticonvulsants were not yet in the picture, KD was introduced as a treatment for epilepsy in children. Before prescribing KD, physicians used starvation as a tool to manage epilepsy but while starvation lessened seizures, patients became malnourished. 

Back in 1921, the endocrinologist Rollin Woodyatt discovered the presence of ketone bodies in both starved patients and patients prescribed a “low-carbohydrate, high-fat” diet.² At the same time, Dr. Wilder stated that the benefits of ketonemia, or having a high level of ketone bodies in the blood, can be achieved other than starvation and this new way is by consuming a high-fat, low-carbohydrate diet to induce ketosis.³ Hence, the KD was created and improved in the years that followed. This was supported by studies showing that both the low sugar and high-fat components of the diet altered the excitability of the brain. It then led to the conclusion that lowered excitability reduced the tendency to generate seizures.⁴

Following the arrival of anticonvulsant medications, KD’s role as the primary management tool for seizures was overshadowed. Eventually, it was relegated to an adjunct therapy, secondary to medication. The KD would then reemerge in the late ‘90s but would not experience a steady rise; physicians still prescribed the diet, but not as a primary intervention.

Decades later, KD resurfaces, this time as a fad diet for people looking to get slimmer. Ketosis, a state in which the body uses fat to generate energy instead of normally utilizing carbohydrates, plays a major role in the weight-loss effects of KD. The KD is structured in such a way that the dieter reaches ketosis in a matter of days or weeks and there is more than one configuration of the ketogenic diet. Current applications reside mostly within the realm of fitness and athletics due to their fat-loss abilities.

Table 1. Ketogenic Diet Types and Composition (Mohan & Shilpa, 2018)

Aside from the management of epilepsy, evidence of the benefit of the ketogenic diet to diabetes mellitus is being studied with its mechanism of potentially reducing blood glucose levels. This moment of resurgence in popularity may lend KD some room for expansion in terms of benefit, as well as pin down some limitations along the way.⁵

Case in Point: Cancer

In the past decades, studies^6,7 have discovered some evidence leading to KD as a therapeutic diet for cancer. Due to how KD works, it has been hypothesized to slow tumor growth and animal studies⁸ have shown that KD may assist with anti-cancer drugs. However, evidence is very limited and scarce as KD has a high dropout rate which makes it difficult to study.

Cancer is characterized by the uncontrollable growth and spread of cancer cells throughout the body.⁹ The starting point of cancer can be anywhere, and its vector is just as unpredictable. Metastasis is when cancer spreads to neighboring organs which usually happens in advanced cancer stages. Moreover, cancers may or may not have lumps or tumors; leukemia, for example, does not present with tumors, since it is a cancer of the blood.

Cancers are classified by stage, grade, and location. The following tables illustrate the staging and grading of cancers, while the graph illustrates the incidence and mortality rates of the most common cancers in the Philippines in 2018.¹⁰

Table 2. Stages of Cancer (NHS Choices, n.d.)

Table 3. Grades of Cancer (NHS Choices, n.d.)

Figure 1. Most common cancers in the Philippines in 2018 (WHO, 2020)

So, how does it work?

The rationale behind KD as a therapeutic diet for cancer lies in how it can trigger the Warburg effect. The Warburg effect is characterized by the shift of glucose metabolism from glycolysis (glucose to pyruvate) to the lactic acid formation (anaerobic pathway) even in the presence of oxygen in producing adenosine triphosphate (ATP), the cell’s source of energy. 

Some cancers cannot metabolize ketone bodies, which are abundant during ketosis, so the thinking goes KD can “starve” cancer cells while preserving normal cells which can adapt to ketosis. Since KD restricts glucose, cancer cells have a limited substrate for energy metabolism and could consequently limit proliferation.

It is only recently that KD is being studied as cancer therapy for humans. The bulk of the evidence involves animal studies. One study on mice showed decreased tumor growth and prolonged survival by around 17 days.¹¹

Another study on mice showed that a very low-carbohydrate diet prevented the growth of squamous cell carcinoma (SCC) tumors with lung or esophageal cancer, and that tumor growth was less when KD was combined with canagliflozin, a diabetes drug. Furthermore, administering KD boosted the effect of phosphoinositide 3-kinase inhibitors (PI3K inhibitors), a group of anticancer drugs, partly due to the decreased insulin levels secondary to KD.¹²

Ketogenic Diet in Cancer Progression, Remission, and Resurgence

It is important to note that due to cancer being a highly diverse disease, with many different presentations and patterns, there’s not one singular outcome from being prescribed a KD. 

To see the interplay of KD in cancer, there are a number of studies worth checking:

• An article by Jansen & Walach (2016) described an outcome of remission in one patient among four who had been in strict KD since 2009.¹¹ Resurgence was noted when the KD was stopped. 
   
• In two studies on treating glioblastoma with KD, disease progression was reported with similar results. In a case report by Zuccoli et al. (2010), a patient exhibited no discernable brain tissue upon FDG-PET or MRU after two months on a strict 4:1 (fat: carbohydrate + protein) diet.¹³ Tumor recurrence was observed in 10 days following suspension of the KD.
   
• In a study by Schwartz et al. (2015), two patients presented with the progression of glioblastoma following an energy-restricted KD (ERKD).¹⁴ The authors stated that these were due to the target glucose ranges of 50-70 mg/dL not being reached. In this same study, the authors compiled articles and case reports that showed prolonged remissions ranging from more than 5 years to 4 months in 30 glioma patients treated with KD.

Ketogenic Diet in Weight and Body Composition

As for other studies, weight and body composition are cited as health outcomes of cancer patients being treated with KD. 

• In Zuccoli et al. (2010) study, strict ERKD induced 20% weight loss in patients with glioblastoma.¹³ 
   
• In a prospective study by Klement & Sweeney (2016) on six cancer patients, two patients had significant weight losses.¹⁵
   
• In Klement, Schafer & Sweeny (2020) study on patients with rectal, breast, and head & neck cancer (HNC) treated with radiotherapy (n=20) compared with control (n=61), KD was significantly associated with losses of 0.5 and 0.4 kg fat mass per week.¹⁶ While fat-free and skeletal masses were not significantly changed in patients with rectal and breast cancers, weight gain was significantly associated with KD in weight and fat-free and skeletal muscle masses for HNC patients, in terms of body composition.

Ketogenic Diet in Quality of Life and Dietary Compliance

Quality of life (QoL) was also considered in the above-cited studies. In Schmidt et al. (2011) study, QoL did not increase and instead remained stable or even worsened.¹⁷ A total of 9 out of the 16 patients dropped out because of inability to tolerate KD within three days, personal reasons, inability to follow the diet regimen, and because the disease progressed after 6-8 weeks. 

Here are other studies focusing on KD success and sustainability rate:

• Cohen et al. (2019) reported only 57%-80% adherence to KD in patients with ovarian and endometrial cancer.¹⁸
   
• In Rieger et al. (2014) study, three patients with glioblastoma dropped out due to diet intolerance, although no serious adverse conditions were noted from all subjects.¹⁹
   
•  Six patients with cancer in Klement & Sweeney (2016) study reported no adverse conditions, and there even was a consensus that the KD was “satiating”.¹⁵
   
• Ok et al. (2018) noted similar feedback from their 10 patients under KD. Moreover, the patients showed better meal compliance, energy intake rate, and meal satisfaction scores than those of the controls.²⁰
   
• In a study by Iyikesici (2019a), patients with metastatic non-small cell lung cancer showed no adverse reactions to metabolically supported chemotherapy (MSCT), ketogenic diet, hyperthermia, and hyperbaric oxygen therapy (HBOT) although the study did not include controls.²¹ 
   
• Similar feedback was extrapolated by Iyikesici (2019b) in a different study on patients with metastatic pancreatic cancer. Specific parameters, such as QoL, emotional functioning, social functioning, sleep quality, future perspectives, and systemic therapy side effects were also improved in the 29 patients in the study.²²
   
• Dietary compliance deteriorated at the end of the study by Klement, Weigel & Sweeney (2021).²³ 
   
• Lastly, Khodabakshi et al. (2020) reported insignificant differences in QoL and physical activity between the experimental and control groups (n=40).²⁴

Verdict: Can Keto Cure Cancer?

There is a lot of skepticism surrounding KD as an adjunct treatment for cancer.²⁵ It may be shortsighted to take KD off the table simply because it may lead to weight loss in patients, because the weight loss may not entirely affect the survival rate in patients with cancer. 

Moreover, studies have shown a higher probability of KD having anti-tumor effects. Therefore, while there is a paucity of high-quality studies on KD as a therapeutic diet for managing and treating cancer, paucity or lack must not be equated to the absence of evidence.²⁶

It needs to be emphasized that lack of evidence has prevented KD from being recommended by medical societies as an adjunct therapy for cancers. Additionally, the handful of studies on KD has small sample sizes. With regards to the diet itself, KD remains an unsustainable diet for patients, and the mechanism by which it benefits cancer remains unclear. The highly varied effects it has on different cancer cases do not strengthen its case as a potential adjunct therapy.²⁷

The ‘for’ and ‘against’ sides have undeniable shortcomings, but there’s one way that they can come together. The interplay of these opposing sides points to crafting an individualized plan of care for the patient, one that factors in the condition, preferences, and resources of the patient; familiarity of the care providers with the available treatment options; and scientific evidence. Given that KD is a relatively new treatment in the realm of cancer, medical societies are rightfully being careful.

Message from Mr. Andal to fellow Nutritionist-Dietitians

The foundation of health is nutrition and therefore, we, nutritionist-dietitians play a huge role in attending to the needs of our patients in disease prevention and management. Medical interventions will not achieve optimal success if the patient is not receiving adequate nutrition care. I hope Pinoy RNDs will be more proactive in advocating the importance of incorporating nutrition in the medical management of diseases - we have so much to offer and add to the standards of medical care! May we continue to strive for a vision of a healthier Philippines through health and nutrition. Our work will never end as long as patients are dying from the consequences of malnutrition.