Feasibility, Safety, and Beneficial Effects of MCT-Based Ketogenic Diet for Breast Cancer Treatment: A Randomized Controlled Trial Study.

The present study was aimed to evaluate the safety, tolerability, and beneficial effects of a ketogenic diet (KD) on body composition and blood parameters and survival in patients with breast cancer. In this randomized, controlled trial, 60 patients with locally advanced or metastatic breast cancer and planned chemotherapy, were randomly assigned to a group receiving KDs (n = 30) or to a control group with standard diet (n = 30) for 3 months. Serum biochemical parameters and body composition were analyzed at baseline, every 3 weeks and end of each arm. Compliance and safety of KD were also checked weekly. Fasting blood sugar (FBS) was significantly decreased in intervention group compared to the baseline (84.5 ± 11.3 vs. 100.4 ± 11.8, P = 0.001). A significant inter-group difference was also observed for FBS level at end of intervention. There was an increasing trend in serum levels of ketone bodies in intervention group (0.007-0.92, P < 0.001). Compared to the control group, BMI, body weight, and fat% were significantly decreased in intervention group in last visit (P < 0.001). No severe adverse side effect was found regarding lipid profile and kidney or liver marker. Overall survival was higher in KD group compared to the control group in neoadjuvant patients (P = 0.04). Our results suggested that chemotherapy combined with KDs can improve the biochemical parameters, body composition, and overall survival with no substantial side effects in patients with breast cancer.

Does a ketogenic diet have beneficial effects on quality of life, physical activity or biomarkers in patients with breast cancer: a randomized controlled clinical trial.

INTRODUCTION: Despite recent interest in the use of ketogenic diets (KDs) for cancer, evidence of beneficial effects is lacking. This study examined the impact of a randomly assigned KD on quality of life, physical activity and biomarkers in patients with breast cancer. METHOD: A total of 80 patients with locally advanced or metastatic breast cancer and without a history of renal disease or diabetes were randomly assigned to either a KD or a control group for this 12-week trial. Concurrent with the first, third, and fifth chemotherapy sessions, quality of life, physical activity, and biomarkers (thyroid function tests, electrolytes, albumin, ammonia, ALP, lactate and serum ketones) were assessed. Dietary intake was also recorded on admission and the end of the treatment. RESULTS: No significant differences were seen in quality of life or physical activity scores between the two groups after 12 weeks; however, the KD group showed higher global quality of life and physical activity scores compared to the control group at 6 weeks (P = 0.02 P = 0.01). Also, serum lactate and ALP levels decreased significantly in the KD group compared to the control group at the end of the intervention (10.7 ± 3 vs 13.3 ± 4, 149 ± 71 vs 240 ± 164, P = 0.02 and P = 0.007, respectively). A significant inverse association was observed between total carbohydrate intake and serum beta-hydroxybutyrate at 12 weeks (r = - 0.77 P < 0.001). No significant differences between groups were observed in thyroid hormones, electrolytes, albumin, LDH or ammonia. Compliance among KD subjects ranged from 66.7 to 79.2% as assessed by dietary intake and serum ketones levels of > 0.5. CONCLUSION: According to our results, besides a higher global quality of life and physical activity scores compared to the control group at 6 weeks, KD diet combined to chemotherapy in patients with breast cancer does not bring additional benefit about quality of life and physical activity at 12 weeks. However, decreases seen in levels of lactate and ALP in the KD group suggest that a KD may benefit patients with breast cancer. TRIAL REGISTRATION: This trial has been registered on Iranian Registry of Clinical Trials (IRCT) under the identification code: IRCT20171105037259N2 https://www.irct.ir/trial/30755.

Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma?

No major advances have been made in improving overall survival for glioblastoma (GBM) in almost 100 years. The current standard of care (SOC) for GBM involves immediate surgical resection followed by radiotherapy with concomitant temozolomide chemotherapy. Corticosteroid (dexamethasone) is often prescribed to GBM patients to reduce tumor edema and inflammation. The SOC disrupts the glutamate-glutamine cycle thus increasing availability of glucose and glutamine in the tumor microenvironment. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive GBM growth through substrate level phosphorylation in the cytoplasm and the mitochondria, respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability while elevating ketone bodies that are neuroprotective and non-fermentable. Information is presented from preclinical and case report studies showing how KMT could target tumor cells without causing neurochemical damage thus improving progression free and overall survival for patients with GBM.

Ketogenic Metabolic Therapy, Without Chemo or Radiation, for the Long-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report.

Background: Successful treatment of glioblastoma (GBM) remains futile despite decades of intense research. GBM is similar to most other malignant cancers in requiring glucose and glutamine for growth, regardless of histological or genetic heterogeneity. Ketogenic metabolic therapy (KMT) is a non-toxic nutritional intervention for cancer management. We report the case of a 32-year-old man who presented in 2014 with seizures and a right frontal lobe tumor on MRI. The tumor cells were immunoreactive with antibodies to the IDH1 (R132H) mutation, P53 (patchy), MIB-1 index (4-6%), and absent ATRX protein expression. DNA analysis showed no evidence of methylation of the MGMT gene promoter. The presence of prominent microvascular proliferation and areas of necrosis were consistent with an IDH-mutant glioblastoma (WHO Grade 4). Methods: The patient refused standard of care (SOC) and steroid medication after initial diagnosis, but was knowledgeable and self-motivated enough to consume a low-carbohydrate ketogenic diet consisting mostly of saturated fats, minimal vegetables, and a variety of meats. The patient used the glucose ketone index calculator to maintain his Glucose Ketone Index (GKI) near 2.0 without body weight loss. Results: The tumor continued to grow slowly without expected vasogenic edema until 2017, when the patient opted for surgical debulking. The enhancing area, centered in the inferior frontal gyrus, was surgically excised. The pathology specimen confirmed IDH1-mutant GBM. Following surgery, the patient continued with a self-administered ketogenic diet to maintain low GKI values, indicative of therapeutic ketosis. At the time of this report (May 2021), the patient remains alive with a good quality of life, except for occasional seizures. MRI continues to show slow interval progression of the tumor. Conclusion: This is the first report of confirmed IDH1-mutant GBM treated with KMT and surgical debulking without chemo- or radiotherapy. The long-term survival of this patient, now at 80 months, could be due in part to a therapeutic metabolic synergy between KMT and the IDH1 mutation that simultaneously target the glycolysis and glutaminolysis pathways that are essential for GBM growth. Further studies are needed to determine if this non-toxic therapeutic strategy could be effective in providing long-term management for other GBM patients with or without IDH mutations.

Metabolically Supported Chemotherapy for Managing End-Stage Breast Cancer: A Complete and Durable Response.

Breast cancer accounts for significant morbidity and mortality worldwide. Currently, treatment options in metastatic breast cancer consist of chemotherapy, along with endocrine, radiation, and/or biological therapies. Although advances in management have improved overall survival times, the treatment options for women with end-stage disease are mostly limited to supportive care. Herein, we present a case report that highlights the response of a 47-year-old premenopausal woman with end-stage (T4N3M1) breast cancer treated with metabolically supported chemotherapy (MSCT), ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen therapy (HBOT). The patient first noticed a right breast mass in late 2016, which was initially evaluated and ruled out as a cyst. Skin ulceration was observed in the region of the suspected cyst in May 2017. Subsequent bilateral breast ultrasound identified masses in both breasts and an enlarged right axillary lymph node. The diagnosis following biopsy was grade 3, estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), human epidermal growth factor receptor 2 negative (HER2-), invasive ductal carcinoma of the breast. Initially, the patient refused to receive conventional chemotherapy because of its potential for side effects and toxicity, but she sought medical treatment in August 2018 following extensive disease progression and deterioration of general health. On reevaluation, the patient was considered ineligible for conventional treatment due to her advanced end-stage disease, poor performance status (Eastern Cooperative Oncology Group score: 3), and advanced respiratory symptoms. Exploring other options, the patient was admitted to the ChemoThermia Oncology Center, Istanbul, Turkey in November 2018. At that time, the patient weighed 38 kg (body mass index: 18.1 kg/m2) and had extensive metastatic disease with lesions in the brain, lungs, mediastinum, liver, abdomen, and bones that were detected by magnetic resonance imaging of the brain (with contrast) and whole-body (18F)-fluorodeoxyglucose-positron emission tomography-computed tomography. The patient received a six-month treatment protocol comprised of MSCT, KD, HT, and HBOT, which eliminated all detectable lesions. The therapeutic response was sustained for two years with maintenance treatment comprising KD, dietary supplements, and repurposed medications. This single case report presents evidence of a complete and durable response to a treatment protocol combining MSCT and a novel metabolic therapy in a patient with end-stage breast cancer.

Effects of Ketogenic metabolic therapy on patients with breast cancer: A randomized controlled clinical trial.

BACKGROUND: Ketogenic metabolic therapy (KMT) using ketogenic diets (KD) is emerging as viable alternative or complementary strategy for managing cancer; however, few clinical trials have been reported. The present study aimed to evaluate the effects of a KD in patients with locally advanced and metastatic breast cancer receiving chemotherapy. METHODS: A total of 80 patients undergoing treatment with chemotherapy were randomly assigned to KD or control group for 12 weeks. Concurrent with the admission, midway point, and at 12 weeks, fasting blood samples were collected for evaluation of insulin, IGF-1, CEA, CA15-3, ESR, CRP, IL-10, and TNF-α. Sonography for patients with locally advanced disease and CT or MRI scans for patients with metastatic disease were done on admission and at 12 weeks. At the completion of the chemotherapy, patients with locally advanced disease underwent surgery and stage was recalculated. Also patients with metastases were evaluated for response rate. RESULTS: TNF-α decreased significantly after 12 weeks of treatment (MD: 0.64 [CI 95%: -3.7, 5] P < 0.001), while IL-10 increased (MD: 0.95 [CI 95%: -1,3] P < 0.001) in the intervention compared to the control group. Patients in the KD group had lower adjusted serum insulin compared to the control group (MD:-1.1 [CI 95%: -3,1] p < 0.002). KD lead to a reduction in tumor size in the KD compared to the control (27 vs 6 mm, P = 0.01). Stage decreased significantly in patients with locally advanced disease in the KD group after 12 weeks (P < 0.01). No significant differences in response rate were observed in patients with metastatic disease. CONCLUSIONS: KMT in breast cancer patients might exert beneficial effects through decreasing TNF-α and insulin and increasing IL-10. KD may result in a better response through reductions in tumor size and downstaging in patients with locally advanced disease; however, more studies are needed to elucidate the potential beneficial effects of KD in patients with metastases. TRIAL REGISTRATION: This trial has been registered on Iranian Registry of Clinical Trials (IRCT) under the identification code: IRCT20171105037259N2. https://www.irct.ir/trial/30755.

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer.

Breast cancer remains as a significant cause of morbidity and mortality in women. Ultrastructural and biochemical evidence from breast biopsy tissue and cancer cells shows mitochondrial abnormalities that are incompatible with energy production through oxidative phosphorylation (OxPhos). Consequently, breast cancer, like most cancers, will become more reliant on substrate level phosphorylation (fermentation) than on oxidative phosphorylation (OxPhos) for growth consistent with the mitochondrial metabolic theory of cancer. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive breast cancer growth through substrate level phosphorylation (SLP) in both the cytoplasm (Warburg effect) and the mitochondria (Q-effect), respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability to tumor cells while simultaneously elevating ketone bodies, a non-fermentable metabolic fuel. It is suggested that KMT would be most effective when used together with glutamine targeting. Information is reviewed for suggesting how KMT could reduce systemic inflammation and target tumor cells without causing damage to normal cells. Implementation of KMT in the clinic could improve progression free and overall survival for patients with breast cancer.

Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up.

Few advances have been made in overall survival for glioblastoma multiforme (GBM) in more than 40 years. Here, we report the case of a 38-year-old man who presented with chronic headache, nausea, and vomiting accompanied by left partial motor seizures and upper left limb weakness. Enhanced brain magnetic resonance imaging revealed a solid cystic lesion in the right partial space suggesting GBM. Serum testing revealed vitamin D deficiency and elevated levels of insulin and triglycerides. Prior to subtotal tumor resection and standard of care (SOC), the patient conducted a 72-h water-only fast. Following the fast, the patient initiated a vitamin/mineral-supplemented ketogenic diet (KD) for 21 days that delivered 900 kcal/day. In addition to radiotherapy, temozolomide chemotherapy, and the KD (increased to 1,500 kcal/day at day 22), the patient received metformin (1,000 mg/day), methylfolate (1,000 mg/day), chloroquine phosphate (150 mg/day), epigallocatechin gallate (400 mg/day), and hyperbaric oxygen therapy (HBOT) (60 min/session, 5 sessions/week at 2.5 ATA). The patient also received levetiracetam (1,500 mg/day). No steroid medication was given at any time. Post-surgical histology confirmed the diagnosis of GBM. Reduced invasion of tumor cells and thick-walled hyalinized blood vessels were also seen suggesting a therapeutic benefit of pre-surgical metabolic therapy. After 9 months treatment with the modified SOC and complimentary ketogenic metabolic therapy (KMT), the patient's body weight was reduced by about 19%. Seizures and left limb weakness resolved. Biomarkers showed reduced blood glucose and elevated levels of urinary ketones with evidence of reduced metabolic activity (choline/N-acetylaspartate ratio) and normalized levels of insulin, triglycerides, and vitamin D. This is the first report of confirmed GBM treated with a modified SOC together with KMT and HBOT, and other targeted metabolic therapies. As rapid regression of GBM is rare following subtotal resection and SOC alone, it is possible that the response observed in this case resulted in part from the modified SOC and other novel treatments. Additional studies are needed to validate the efficacy of KMT administered with alternative approaches that selectively increase oxidative stress in tumor cells while restricting their access to glucose and glutamine. The patient remains in excellent health (Karnofsky Score, 100%) with continued evidence of significant tumor regression.

Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is more aggressive and metastatic than other breast cancer types. Cytotoxic chemotherapy is presently the predominant systemic therapy for TNBC patients. This case report highlights the influence of metabolically supported chemotherapy (MSCT), ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen therapy (HBOT) in an overweight 29-year-old woman with stage IV (T4N3M1) triple-negative invasive ductal carcinoma of the breast. The patient presented with an observable mass in her left breast detected during a physical examination in December 2015. Magnetic resonance imaging revealed a Breast Imaging Reporting and Data System Category 5 tumor and multiple lymphadenomegaly in the left axilla. A Tru-Cut biopsy led to the diagnosis of a triple-negative nuclear grade 2 invasive ductal carcinoma. The patient was admitted to ChemoThermia Oncology Center, Istanbul, Turkey in October 2016, and a whole body (18F)-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT) scan revealed a 77 mm x 55 mm primary tumor in her left breast, multiple left pectoral and axillary lymph nodes, multiple widespread liver masses, and an upper left nodular abdominal lesion. The patient received a treatment protocol consisting of MSCT, KD, HT, and HBOT. A follow-up whole body 18F-FDG PET-CT scan in February 2017 showed a complete therapeutic response with no evidence of abnormal FDG uptake. The patient continued to receive this treatment protocol and in April 2017 underwent a mastectomy, which revealed a complete pathological response consistent with the response indicated by her PET-CT imaging. 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.