The ketogenic diet (KD), characterized by its high-fat and very low carbohydrate content, has garnered significant attention for its potential therapeutic applications, particularly in cancer management. This article explores the history, mechanisms, and current research surrounding the use of KD as an adjuvant to cancer therapy.
Historical Context and Foundations
The use of fasting as a medical treatment dates back to 500 BC. In the early 20th century, fasting was proposed as an antiepilepsy treatment. In 1921, it was observed that a high-fat, low-carbohydrate diet mimicked the effects of starvation, producing acetone and β-hydroxybutyrate, energy sources produced by the liver in the absence of glucose. Wilder and Peterman later coined the term "ketogenic diet," establishing a specific fat-to-carbohydrate ratio that is still used today.
The potential of KD in cancer therapy emerged in 1922 when it was noted that glucose disappeared from the urine of diabetic patients after a cancer diagnosis, suggesting that cancer cells consume glucose at higher rates. Otto Warburg further discovered that cancer cells thrive on glycolysis, producing high lactate levels even in the presence of oxygen.
While KD use waned in the mid-20th century, it regained recognition in the late 1990s with the establishment of the Charlie Foundation.
Metabolic Mechanisms of the Ketogenic Diet
The ketogenic diet mimics a fasting state, where the body responds to a lack of glucose by producing ketones for energy. A standard diet is predominantly made up of carbohydrates and is high in caloric value. In KDs, a high ratio of fat to low carbohydrates mimics the metabolic effects of starvation.
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Glucose normally stimulates pancreatic β cells to release insulin, which allows glucose to enter cells and provide energy. High carbohydrate and glucose intake leads to increased insulin secretion, promoting the production of insulin-like growth factor 1 (IGF-1), which can promote cell growth and proliferation. Many cancers also exhibit overexpression of glucose transporters (Glut-1, Glut-3) and hexokinase, driving glycolysis and causing reactive oxygen species damage.
When glucose is scarce, the liver produces ketones and fatty acids, which can be used by normal cells but are not efficiently utilized by cancer cells due to their dysfunctional mitochondria and electron transport chain defects.
The resulting tumor dependence on glucose can be exploited with KD use. Ketogenic diets slow cancer by inhibiting insulin/IGF and downstream intracellular signaling pathways, such as phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR). Ketogenic diets also amplify adenosine monophosphate-activated protein kinase (AMPK), which inhibits aerobic glycolysis and suppresses tumor proliferation, invasion, and migration.
Clinical Evidence and Research Findings
Several studies and case reports have explored the effects of KD on cancer patients:
- In 1962, two women with metastatic cancers experienced remission after hypoglycemia-induced insulin comas.
- A glioblastoma patient showed a radiographic response and good tumor control for about a year with temozolomide oral chemotherapy and a ketogenic diet.
- Two pediatric astrocytoma patients experienced improved mood and decreased glucose uptake in tumor sites during 8 weeks of ketogenic dieting.
- A feasibility study of the modified Atkins KD in advanced cancer patients with solid tumors showed a correlation between insulin levels and ketosis, with stable disease or partial remission correlating with higher ketosis.
- The ERGO trial studied relapsed glioblastoma patients on KD supplemented with plant oils, finding that quality of life was maintained despite significant weight loss.
- A pilot study provided KD plus oil-protein shakes to patients with advanced metastatic cancers, showing statistically significant mean weight loss, stable blood lipid levels, improved quality of life, and no severe adverse events.
- A safety trial at the VA Pittsburgh Healthcare System enrolled patients, with responders showing a weight loss of ≥ 10% compared with nonresponders.
These findings suggest that KD use is safe and tolerable for patients with cancer, but larger randomized trials are needed.
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Ongoing Clinical Trials
Several clinical trials are currently underway to further investigate the role of KD in cancer treatment:
- Duke University is conducting a randomized study of the Atkins diet and androgen deprivation therapy for prostate cancer patients (NCT00932672).
- Tel Aviv Sourasky Medical Center in Israel is recruiting patients with high-grade glial tumors for an open-label study of KD in preventing tumor growth and recurrence (NCT01092247).
- St. Joseph’s Hospital and Medical Center is recruiting newly diagnosed glioblastoma patients for a phase 1/2 trial involving KD with radiotherapy and concurrent temozolomide (NCT02046187).
Potential Risks and Considerations
While KD has shown promise, it is essential to consider potential risks:
- A recent study in a mouse model of breast cancer found that KD increased lung metastases, dependent on the protein BACH1.
- Higher fat consumption has been associated with poorer long-term outcomes for some cancers, including breast cancer.
- Long-term KD feeding can induce fatty liver and fibrosis.
- In mice with pancreatic and colorectal cancer, keto accelerates a lethal wasting disease called cachexia.
The Gut Microbiome's Role
Recent research highlights the importance of the gut microbiome in the context of KD and cancer.
- KD has been shown to possess anti-cancer properties in the context of colorectal cancer (CRC).
- Cancer progression is accompanied by a state of dysbiosis of the gut microbiome.
- The anti-cancer effects of KD can be mediated by the gut microbiome.
- KD induces a distinct fecal microbial profile.
One study demonstrated that KD led to reduced colonic tumor burden and immune inflammatory response in CRC. Cecal microbial transplantation from KD-fed mice into standard-diet mice resulted in a lower colonic tumor burden.
Dietary Considerations and Recommendations
Experts emphasize that a whole foods, plant-based diet is generally superior to a ketogenic diet for reducing cancer risk. While both keto and plant-based diets have proven effective for weight loss, there is less data available to answer whether the benefits of these diets extend to cancer. MSK has a keto clinical trial called TIFA that is very specifically controlled to avoid those pitfalls. For instance, preprepared meals are delivered to patients so the mix of nutrients is appropriate.
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The Warburg Effect and Cancer Metabolism
Nobel laureate Otto Warburg's discovery that cancer cells primarily rely on glycolysis, even in the presence of oxygen, has significant implications for cancer metabolism. This phenomenon, known as the Warburg effect, is characterized by high glucose consumption and lactate production.
The ketogenic diet, by limiting glucose availability, aims to disrupt this metabolic pathway and starve cancer cells of their primary fuel source.