Ketogenic diet in the treatment of cancer - Where do we stand?
Molecular metabolism
BACKGROUND:Cancer is one of the greatest public health challenges worldwide, and we still lack complementary approaches to significantly enhance the efficacy of standard anticancer therapies. The ketogenic diet, a high-fat, low-carbohydrate diet with adequate amounts of protein, appears to sensitize most cancers to standard treatment by exploiting the reprogramed metabolism of cancer cells, making the diet a promising candidate as an adjuvant cancer therapy. SCOPE OF REVIEW:To critically evaluate available preclinical and clinical evidence regarding the ketogenic diet in the context of cancer therapy. Furthermore, we highlight important mechanisms that could explain the potential antitumor effects of the ketogenic diet. MAJOR CONCLUSIONS:The ketogenic diet probably creates an unfavorable metabolic environment for cancer cells and thus can be regarded as a promising adjuvant as a patient-specific multifactorial therapy. The majority of preclinical and several clinical studies argue for the use of the ketogenic diet in combination with standard therapies based on its potential to enhance the antitumor effects of classic chemo- and radiotherapy, its overall good safety and tolerability and increase in quality of life. However, to further elucidate the mechanisms of the ketogenic diet as a therapy and evaluate its application in clinical practice, more molecular studies as well as uniformly controlled clinical trials are needed.
10.1016/j.molmet.2019.06.026
A Ketogenic Diet Is Acceptable in Women with Ovarian and Endometrial Cancer and Has No Adverse Effects on Blood Lipids: A Randomized, Controlled Trial.
Cohen Caroline W,Fontaine Kevin R,Arend Rebecca C,Gower Barbara A
Nutrition and cancer
Ketogenic diets (KDs) are emerging as effective therapies for several chronic diseases, including cancer. However, concerns regarding safety and adherence may prevent clinicians from prescribing KDs. We hypothesized that a KD does not negatively affect blood lipid profile compared to a lower-fat diet in ovarian and endometrial cancer patients, and that KD subjects would demonstrate acceptable adherence. Subjects were randomized to either a KD (70% fat, 25% protein, 5% carbohydrate), or the American Cancer Society diet (ACS; high-fiber and lower-fat). Blood lipids and ketones were measured at baseline and after 12 weeks of the assigned intervention. Adherence measures included urinary ketones in the KD and 4 days' diet records. Diet records were also examined to identify general patterns of consumption. Differences between the diets on blood lipids and dietary intake were assessed with Analysis of covariance and independent -tests. Correlation analyses were used to estimate associations between dietary intake and serum analytes. At 12 weeks, there were no significant differences between diet groups in blood lipids, after adjusting for baseline values and weight loss. Adherence among KD subjects ranged from 57% to 80%. These findings suggest that KDs may be a safe and achievable component of treatment for some cancer patients.
10.1080/01635581.2019.1645864
Dietary Energy Density, Glycemic Load, Glycemic Index, and Risk for Endometrial Cancer in the CPS-II Nutrition Cohort.
Hartman Terryl J,McCullough Marjorie L,Hodge James M,Gaudet Mia M,Wang Ying,Gapstur Susan M
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
The glycemic potential and energy density (ED) of diet may influence endometrial cancer risk. Although glycemic load (GL) is considered a probable risk factor for endometrial cancer, no studies have evaluated the association of total dietary ED with risk. We evaluated associations of ED, GL, and glycemic index (GI) with postmenopausal endometrial cancer incidence. Analyses included 30,997 postmenopausal women from the Cancer Prevention Study II Nutrition Cohort with no previous history of cancer or diabetes, who provided information on diet, lifestyle, and medical history in 1999 and were followed for cancer incidence through June 2013. Multivariable-adjusted HRs and 95% confidence intervals were estimated for quartiles (Q) of total dietary ED, GL, and GI in relation to endometrial cancer incidence using Cox proportional hazards regression models. During a median follow-up time of 13.6 years, 425 endometrial cancer cases were identified. Median dietary ED was 1.5 kcal/g [interquartile range (IQR) = 1.3-1.7 kcal/g]. Median (IQR) GL and GI were 113.7 (100.5-126.8) and 52.5 (50.4-54.5), respectively. After adjustment for age, use of hormone replacement therapy, physical activity, and body mass index (kg/m), neither ED, GL, nor GI were associated with endometrial cancer risk. We found no associations of ED, GL, or GI with endometrial cancer risk. These results do not support an association between total dietary ED, GL, or GI and risk of postmenopausal endometrial cancer. .
10.1158/1055-9965.EPI-17-0964
Diet and risk of breast, endometrial and ovarian cancer: UK Women's Cohort Study.
Dunneram Yashvee,Greenwood Darren C,Cade Janet E
The British journal of nutrition
This study aimed to investigate the association between diet and the risk of breast, endometrial and ovarian cancer in the UK Women's Cohort Study. A total of 35 372 women aged 35-69 years were enrolled between 1995 and 1998 and completed a validated 217-item FFQ. The individual foods were collapsed into sixty-four main food groups and compared using Cox proportional models, adjusting for potential confounders. Hazard ratio (HR) estimates are presented per portion increase in food items. After approximately 18 years of follow-up, there were 1822, 294 and 285 cases of breast, endometrial and ovarian cancer, respectively. A high consumption of processed meat and total meat was associated with an increased risk of breast and endometrial cancer. High intake of tomatoes (HR 0·87, 99 % CI 0·75, 1·00) and dried fruits (HR 0·60, 99 % CI 0·37, 0·97) was associated with a reduced risk of breast and endometrial cancer, respectively. Mushroom intake was associated with a higher risk of ovarian cancer (HR 1·57, 99 % CI 1·09, 2·26). Subgroup analysis by pre- or postmenopausal cancer further demonstrated an association between processed meat intake and both postmenopausal breast cancer and endometrial cancer. Intake of dried fruits was associated with a reduced risk of postmenopausal endometrial cancer (HR 0·55, 99 % CI 0·31, 0·98). Our findings suggest that while some foods may trigger the risk of these cancers, some foods may also be protective; supporting the call for further randomised controlled trials of dietary interventions to reduce the risk of cancer among pre- and postmenopausal women.
10.1017/S0007114518003665
Body mass index and attitudes towards health behaviors among women with endometrial cancer before and after treatment.
Harrison Ross,Zhao Hui,Sun Charlotte C,Fu Shuangshuang,Armbruster Shannon D,Westin Shannon Neville,Rauh-Hain Jose Alejandro,Lu Karen H,Giordano Sharon H,Meyer Larissa A
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
INTRODUCTION:Some experts have argued that obesity-related malignancies such as endometrial cancer are a "teachable moment" that lead to meaningful changes in health behaviors. It is unclear if endometrial cancer survivors lose weight following treatment. Our goal with this investigation was to evaluate post-treatment changes in body mass index (BMI) and attitudes towards health behaviors in endometrial cancer survivors. METHODS:Incident endometrial cancer cases undergoing surgery between 2009-2015 were identified in the Marketscan Commercial database and linked with BMI data and health behavior questionnaires from the Marketscan Health Risk Assessment database. Patients were excluded for insufficient BMI data. Standard statistical methods, including the two-sample Wilcoxon rank sum test, χ test, and McNemar's test, were used. RESULTS:655 patients with a median age of 54 (IQR 49-58) were identified and analyzed. Median duration of follow-up was 595 days (IQR 360-1091). Mean pre- and post-treatment BMI was 35.5 kg/m (median 35.0; IQR 27.0-42.3) and 35.6 kg/m (median 34.3; IQR 28.0-42.0), respectively. Median BMI change in the entire cohort was 0 kg/m (IQR -1.0 to 2.0). Weight gain (n=302; 46.1%) or no change in weight (n=106; 16.2%) was seen in most patients. Among the 302 patients who gained weight, the mean pre-treatment BMI was 34.0 kg/m and mean increase was 2.8 kg/m (median 2.0; IQR 1.0-3.4). Among the 247 cases who lost weight, the mean pre-treatment BMI was 38.6 kg/m and mean decrease was 3.2 kg/m (median 2.0; IQR 1.0-4.0). No pre- to post-treatment differences were observed in health behavior questionnaires regarding intention to better manage their diet, exercise more, or lose weight. DISCUSSION:Most endometrial cancer survivors gain weight or maintain the same weight following treatment. No post-treatment changes in attitudes regarding weight-related behaviors were observed. The systematic delivery of evidence-based weight loss interventions should be a priority for survivors of endometrial cancer.
10.1136/ijgc-2019-000999
A Ketogenic Diet Reduces Central Obesity and Serum Insulin in Women with Ovarian or Endometrial Cancer.
The Journal of nutrition
Background:The glycolytic nature of cancer cells presents a potential treatment target that may be addressed by a ketogenic diet (KD). Objective:We hypothesized that a KD would improve body composition and lower serum insulin and insulin-like growth factor-I (IGF-I) in women with ovarian or endometrial cancer. Methods:In this randomized controlled trial, women with ovarian or endometrial cancer [age: ≥19 y; body mass index (kg/m2): ≥18.5] were randomly assigned to a KD (70:25:5 energy from fat, protein, and carbohydrate) or the American Cancer Society diet (ACS; high-fiber, low-fat). Body composition (DXA) and fasting serum insulin, IGF-I, and β-hydroxybutyrate were obtained at baseline and at 12 wk; urinary ketones were also measured throughout the intervention. We assessed differences between the diets with ANCOVA and independent t tests. We used correlation analyses to estimate associations between changes in serum analytes and body composition. Results:After 12 wk, the KD (compared with ACS) group had lower adjusted total (35.3 compared with 38.0 kg, P < 0.05) and android (3.0 compared with 3.3 kg, P < 0.05) fat mass. Percentage of change in visceral fat was greater in the KD group (compared with the ACS group; -21.2% compared with -4.6%, P < 0.05). Adjusted total lean mass did not differ between the groups. The KD (compared with ACS) group had lower adjusted fasting serum insulin (7.6 compared with 11.2 µU/mL, P < 0.01). There was a significant inverse association between the changes in serum β-hydroxybutyrate and IGF-I concentrations (r = -0.57; P < 0.0001). Conclusions:In women with ovarian or endometrial cancer, a KD results in selective loss of fat mass and retention of lean mass. Visceral fat mass and fasting serum insulin also are reduced by the KD, perhaps owing to enhanced insulin sensitivity. Elevated serum β-hydroxybutyrate may reflect a metabolic environment inhospitable to cancer proliferation. This trial was registered at www.clinicaltrials.gov as NCT03171506.
10.1093/jn/nxy119
A prospective analysis of diet quality and endometrial cancer among 84,415 postmenopausal women in the Women's Health Initiative.
Annals of epidemiology
PURPOSE:Endometrial cancer is the most commonly diagnosed gynecologic cancer, but no convincing dietary risk factors for this cancer have been identified. Among postmenopausal women, we examined how four key a priori diet quality indices--the Healthy Eating Index-2010, Alternative Healthy Eating Index-2010, alternate Mediterranean Diet, and Dietary Approaches to Stop Hypertension are related to the risk of endometrial cancer in the Women's Health Initiative Clinical Trials and Observational Study. METHODS:Our prospective cohort study included 84,415 postmenopausal women with a uterus who completed a food frequency questionnaire at enrollment. Cox proportional hazards models were used to estimate multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for endometrial cancer associated with increasing quintiles of diet quality index scores. RESULTS:During 13.3 years of follow-up, 1392 endometrial cancer cases occurred. After adjustment for known risk factors, having better diet quality (Q5 vs. Q1) was not associated with the risk of endometrial cancer, as evidenced using Healthy Eating Index-2010 (HR: 1.11, 95% CI: 0.93-1.33), Alternative Healthy Eating Index-2010 (HR: 0.98, 95% CI: 0.82-1.17), alternate Mediterranean Diet (HR: 0.98, 95% CI: 0.82-1.17), or Dietary Approaches to Stop Hypertension (HR: 1.00, 95% CI: 0.84-1.19). CONCLUSIONS:Diet quality was not associated with endometrial cancer risk in this large cohort of postmenopausal women.
10.1016/j.annepidem.2015.05.009
Dietary inflammatory index, risk and survival among women with endometrial cancer.
Nagle C M,Ibiebele T,Shivappa N,Hébert J R,Spurdle A B,Webb P M,
Cancer causes & control : CCC
PURPOSE:Chronic inflammation has been implicated in endometrial carcinogenesis yet the impact of potentially modifiable exposures that might affect inflammation, like diet, has been understudied. This study examined the association between the dietary inflammatory index (DII®), a literature-derived tool to assess the inflammatory potential of diet, and risk of developing, and survival after a diagnosis of endometrial cancer (EC). METHODS:This study included data from 1,287 women with EC and 1,435 population controls who participated in the Australian National Endometrial Cancer Study. Energy-adjusted DII (E-DII) scores were calculated from pre-diagnostic dietary intake obtained using a semi-quantitative food frequency questionnaire. Logistic regression was used to assess the association between E-DII scores and risk of EC and proportional-hazards models were used for survival analyses. RESULTS:Higher E-DII scores, reflecting a more pro-inflammatory diet, were not associated with risk of EC [adjusted odds ratio (OR) 0.98, 95% CI 0.77-1.24, p-trend = 0.7]. However, in stratified analyses, higher E-DII scores were associated with increased risk of EC among very obese (BMI 35 + kg/m) women (OR 1.60, 95% CI 0.80-3.21, p-trend = 0.049, p-interaction = 0.045). After a median follow-up of 7.2 years there were 160 deaths, of which 110 (69%) were from EC. We found no association between E-DII score and survival. CONCLUSION:Greater inflammatory potential of pre-diagnostic diet was not associated with EC risk or survival. Secondary stratified analysis suggested greater inflammatory potential may be associated with EC risk in very obese women.
10.1007/s10552-019-01257-0
Diet, physical activity, and health-related outcomes of endometrial cancer survivors in a behavioral lifestyle program: the Diet and Exercise in Uterine Cancer Survivors (DEUS) parallel randomized controlled pilot trial.
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
OBJECTIVES:To explore the effectiveness of a theory-based behavioral lifestyle intervention on health behaviors and quality of life in endometrial cancer survivors.' METHODS:This was a secondary analysis of a randomized controlled pilot trial conducted in two UK hospitals enrolling disease-free stage I-IVA endometrial cancer survivors. Participants were allocated to an 8-week group-based healthy eating and physical activity intervention or usual care using 1:1 minimization. Participants were followed up at 8 and 24 weeks, with the 8-week assessment being blinded. Diet, physical activity, and quality of life were measured with the Alternative Healthy Eating Index 2010, Stanford 7-Day Physical Activity Recall, and the EORTC Quality of life Questionnaire Core 30, respectively. We analyzed all eligible participants using the intention-to-treat approach in complete cases, adjusting for baseline values, body mass index, and age. RESULTS:We enrolled 60 of the 296 potentially eligible endometrial cancer survivors (May - December 2015). Fifty-four eligible participants were randomized to the intervention (n=29) or usual care (n=31), and 49 had complete follow-up data (n=24 in the intervention and n= 25 in usual care). Intervention adherence was 77%. At 8 weeks, participants in the intervention improved their diet compared to usual care (difference in Alternative Healthy Eating Index 2010 score 7.5 (95% CI: 0.1 to 14.9), P=0.046) but not their physical activity (0.1 metabolic equivalent-h/day 95% CI: (-1.6 to 1.8), P=0.879), or global quality of life score (5.0 (95% CI: -3.4 to 13.3), P=0.236). Global quality of life improved in intervention participants at 24 weeks (difference 8.9 (95% CI: 0.9 to 16.8), P=0.029). No intervention-related adverse events were reported. CONCLUSIONS:The potential effectiveness of the intervention appeared promising. A future fully-powered study is needed to confirm these findings. TRIAL REGISTRATION NUMBER:NCT02433080.
10.1136/ijgc-2018-000039
Favorable Effects of a Ketogenic Diet on Physical Function, Perceived Energy, and Food Cravings in Women with Ovarian or Endometrial Cancer: A Randomized, Controlled Trial.
Nutrients
Ketogenic diets (KDs) are gaining attention as a potential adjuvant therapy for cancer, but data are limited for KDs' effects on quality of life. We hypothesized that the KD would (1) improve mental and physical function, including energy levels, (2) reduce hunger, and (3) diminish sweet and starchy food cravings in women with ovarian or endometrial cancer. Participants were randomized to a KD (70:25:5 energy from fat, protein, and carbohydrate) or the American Cancer Society diet (ACS: high-fiber, lower-fat). Questionnaires were administered at baseline and after 12 weeks on the assigned diet to assess changes in mental and physical health, perceived energy, appetite, and food cravings. We assessed both between-group differences and within-group changes using ANCOVA and paired -tests, respectively. After 12 weeks, there was a significant between-group difference in adjusted physical function scores ( < 0.05), and KD participants not receiving chemotherapy reported a significant within-group reduction in fatigue ( < 0.05). There were no significant between-group differences in mental function, hunger, or appetite. There was a significant between-group difference in adjusted cravings for starchy foods and fast food fats at 12 weeks ( < 0.05 for both), with the KD group demonstrating less frequent cravings than the ACS. In conclusion, in women with ovarian or endometrial cancer, a KD does not negatively affect quality of life and in fact may improve physical function, increase energy, and diminish specific food cravings. This trial was registered at ClinicalTrials.gov as NCT03171506.
10.3390/nu10091187
Diet and endometrial cancer: a focus on the role of fruit and vegetable intake, Mediterranean diet and dietary inflammatory index in the endometrial cancer risk.
Ricceri Fulvio,Giraudo Maria Teresa,Fasanelli Francesca,Milanese Dario,Sciannameo Veronica,Fiorini Laura,Sacerdote Carlotta
BMC cancer
BACKGROUND:Endometrial cancer is the fourth most common cancer in European women. The major risk factors for endometrial cancer are related to the exposure of endometrium to estrogens not opposed to progestogens, that can lead to a chronic endometrial inflammation. Diet may play a role in cancer risk by modulating chronic inflammation. METHODS:In the framework of a case-control study, we recruited 297 women with newly diagnosed endometrial cancer and 307 controls from Northern Italy. Using logistic regression, we investigated the role of fruit and vegetable intake, adherence to the Mediterranean diet (MD), and the dietary inflammatory index (DII) in endometrial cancer risk. RESULTS:Women in the highest quintile of vegetable intake had a statistically significantly lower endometrial cancer risk (adjusted OR 5th quintile vs 1st quintile: 0.34, 95% CI 0.17-0.68). Women with high adherence to the MD had a risk of endometrial cancer that was about half that of women with low adherence to the MD (adjusted OR: 0.51, 95% CI 0.39-0.86). A protective effect was detected for all the lower quintiles of DII, with the highest protective effect seen for the lowest quintile (adjusted OR 5th quintile vs 1st quintile: 3.28, 95% CI 1.30-8.26). CONCLUSIONS:These results suggest that high vegetable intake, adherence to the MD, and a low DII are related to a lower endometrial cancer risk, with several putative connected biological mechanisms that strengthen the biological plausibility of this association.
10.1186/s12885-017-3754-y
Diet and exercise in uterine cancer survivors (DEUS pilot) - piloting a healthy eating and physical activity program: study protocol for a randomized controlled trial.
Koutoukidis Dimitrios A,Beeken Rebecca J,Manchanda Ranjit,Burnell Matthew,Knobf M Tish,Lanceley Anne
Trials
BACKGROUND:Endometrial cancer survivors comprise a high-risk group for obesity-related comorbidities. Healthy eating and physical activity can lead to better health and well-being, but this population may experience difficulties adopting healthy lifestyle practices. Personalised behaviour change programmes that are feasible, acceptable and cost-effective are needed. The aim of this trial is to pilot a manualised programme about healthy eating and physical activity. METHODS/DESIGN:This is a phase II, individually randomized, parallel, controlled, two-site, pilot clinical trial. Adult endometrial cancer survivors (n = 64) who have been diagnosed with endometrial cancer within the previous 3 years and are not on active treatment will be invited to participate. Participants will be assigned in a 1:1 ratio through minimisation to either an 8-week, group-based, behaviour-change programme with weekly 90-min sessions about healthy eating and physical activity or usual care. The intervention will focus on self-monitoring, goal setting and self-rewards. Follow-up assessments will be conducted at 8 and 24 weeks from the baseline assessment. Primary feasibility outcomes will include rates of recruitment, adherence, and retention. DISCUSSION:The study results will inform the development of a definitive randomised controlled trial to test if the programme can improve the health and quality of life of this population. It will also provide guidance on costing the intervention and the health care resource use in this population. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT02433080, 20 April 2015.
10.1186/s13063-016-1260-1