Although ketogenic diets (KDs) have been in medical use for almost a century in pharmacoresistant epilepsy, it is only in recent years that KDs have been considered as an adjuvant therapy for cancer. As in fasting, KDs shift the body’s fuel source from carbohydrate to fat, reducing blood glucose and insulin while increasing ketone bodies, the byproducts of fatty acid metabolism. These low-carbohydrate, high-fat diets present a metabolic disadvantage to cancer cells due to their dependence on aerobic glycolysis for fuel acquisition and, unlike normal cells, most types of cancer cells are unable to metabolize ketones for energy [1
]. Accordingly, KDs exploit the Warburg effect to “starve” cancer cells of the glucose and insulin required for proliferation.
Despite the growing evidence of KDs’ possible anti-tumor benefits, reluctance still exists from healthcare providers to prescribe this dietary regimen for cancer patients. Concerns relate to the perceived restrictive nature of KDs and their potential to detract from quality of life in a patient population already facing considerable physical and emotional stress. However, there is almost no research evidence evaluating these concerns. Indeed, the literature examining KDs in cancer patients is sparse, and even fewer studies have included mental or physical functioning in their research outcomes. A recent systematic review [3
] of studies examining KD in adult patients with cancer found only three previous studies that have assessed quality of life outcomes, highlighting the need for additional, larger investigations in this field.
Although there are several potential alterations to physical and mental functioning during cancer and its treatment, perhaps the most common is cancer-related fatigue (CRF). The estimated prevalence of CRF ranges from 25% to 99% in patients undergoing treatment, and up to 30% of patients continue to report feeling fatigued years after successful treatment of their disease [4
]. This phenomenon may extend to gynecological cancers; a small, qualitative study of symptom burden in ovarian cancer patients reported that 93% of the women experienced fatigue as a symptom prior to and during cancer treatments [8
]. In addition, a considerable proportion of cancer patients report CRF to be moderate to severe in intensity, ranging from 29% among cancer survivors up to 45% of patients undergoing active treatment [7
]. Interventions for CRF have included psychosocial strategies, exercise, yoga, acupuncture, massage therapy, as well as pharmacologic options, including psychostimulants and antidepressants [9
]. However, despite the prevalence, severity, and potential duration of CRF, almost no research has focused on dietary interventions as a possible means to ameliorate fatigue.
Although the evidence available is limited, previous research suggests that KDs may improve physical and mental well-being. A small trial among advanced cancer patients found that insomnia and emotional functioning improved over the course of a three-month KD intervention, and case reports also reflect enhanced cognitive function [11
]. In regard to fatigue, a low-glycemic-load (though not ketogenic) diet has been associated with significantly lower reported fatigue when compared to a high-glycemic load diet in overweight and obese adults [14
]. Previous research also indicates that low-carbohydrate diets do not increase hunger, as many presume, but rather reduce feelings of hunger as well as sweet and starchy food cravings [15
The purpose of the present analysis was to evaluate and compare the effects of a KD and the lower-fat, American Cancer Society diet (ACS) on physical and mental health status, hunger and satiety, and food cravings in women with ovarian or endometrial cancer. Questionnaire data were obtained from a parallel-arm, randomized, controlled trial; results related to body composition and glucose metabolism from this trial have been previously reported [18
]. We tested the hypothesis that, relative to the ACS, the KD would improve mental and physical function, including energy levels; reduce hunger; and diminish sweet and starchy food cravings in this patient population.
KDs result in several metabolic changes that may cause stress to cancer cells. However, clinical trials examining KDs’ anti-cancer effects are limited, and even fewer studies within this field have analyzed changes in quality of life, hunger, and food cravings. In this investigation, we tested the hypothesis that the KD would improve mental and physical function, reduce hunger, and diminish sweet and starchy food cravings in women with ovarian or endometrial cancer. Our results indicated that, compared to the ACS, the KD improved perceived physical functional status as well as reduced cravings for starchy food and fast food fats. Those in the KD group not receiving chemotherapy also reported significantly more energy at 12 weeks compared to baseline. These findings suggest that a KD is feasible for cancer patients, and may provide several benefits that improve quality of life.
As noted, the PCS of the SF-12 was significantly higher in the KD than that of the ACS after the 12-week diet intervention. Previous studies have indicated that decreases in physical function coincide with increased mortality and morbidity in cancer survivors [28
]. Moreover, the KD resulted in a clinically important improvement in physical status. Previous studies of patients with chronic conditions, including cancer, have estimated that a 2- to 5-point change in PCS may be considered clinically meaningful [30
]; the mean difference in PCS for the KD group in this sample was approximately 4 points. Future investigations might examine whether such diet-induced improvements in physical function might reduce morbidity and mortality. Although the MCS did not differ significantly between the two diet groups, scores in both groups were comparable if not higher than those observed in other samples of cancer patients as well as healthy cancer-free adults [19
]. Thus, an increase in MCS may have been difficult to achieve due to a ceiling effect. Nonetheless, it seems clear that neither dietary regimen (i.e., neither low-fat nor low-carbohydrate) negatively impacted mental well-being.
In subgroup analyses, the KD also increased energy in women not receiving concurrent chemotherapy over the course of the 12-week intervention. An often mentioned benefit of KDs among adherents is heightened and stabilized energy levels [35
]. It has been hypothesized that this energizing effect is related to elevated ketone bodies, although we did not find a significant association between serum BHB and reported energy level in this sample. The effect on energy levels was limited to women not receiving chemotherapy during the diet intervention, which may be due to the fact that women in active treatment may be in more advanced stages of the disease. Alternatively, it is possible that the energizing benefits of the KD were reduced in the context of chemotherapy, the side effects of which often include fatigue. As described above, research examining the potential relationship between diet and CRF is limited and not focused on macronutrient composition. Our findings suggest that carbohydrate restriction merits continued investigation to determine its potential role in mitigating CRF.
There were no significant differences between or within the diet groups for perceived hunger, satisfaction, fullness, or prospective food consumption on the VAS. These results contradict findings from previous, larger investigations in overweight and obese adults, which indicate that low-carbohydrate diets result in reduced hunger when compared to low-fat diets [15
]. A systematic review of the literature related to KDs also revealed that adherents reported less hunger and a reduced desire to eat, even in the context of energy restriction [16
]. Discrepancies in our results from the aforementioned studies may relate to the timing of the administration of the questionnaires. All participants completed the VAS at a single time point during each visit, in a fasted state. Multiple administrations of the VAS (e.g., before and after a test meal) may have provided more insight into each diet’s effect on appetite. Additionally, participants were not provided specific calorie goals during the diet intervention, so it is possible that there was considerable variation in terms of whether participants were in positive or negative energy balance throughout the study, which may in turn have influenced feelings of hunger or satiety. Nonetheless, our findings suggest that a KD does not adversely affect hunger and appetite and thus is not any more restrictive than other conventional diets.
Responses to the VAS and FCI also revealed that the KD group experienced significant changes in food cravings. First, the KD resulted in significantly higher cravings for salty foods compared to the ACS. The decrease in insulin levels and increase in ketone bodies that typically accompany KDs may cause a natriuretic effect [36
]. Thus, this observation may be a manifestation of sodium depletion in the KD. After 12 weeks of the diet intervention, there were significant between-group differences in cravings for starchy foods and fast food fats, and within the KD group, there were significant reductions in cravings for starchy foods, sweets, fast food fats, and overall cravings at 12 weeks compared to baseline. These findings are similar to those of a two-year clinical trial in which obese adults were assigned to either a low-carbohydrate or low-fat diet. Those in the low-carbohydrate group experienced significantly greater decreases in cravings for starchy foods, sweets, and fast food fats in comparison to the low-fat group, whereas the low-fat group reported decreases in cravings for high-fat foods, suggesting that adherents of any given diet may crave restricted foods less frequently [17
]. In the present study, it is clear that the KD generated less frequent cravings across several food categories, many of which offer limited nutritional value other than energy. Accordingly, it is possible that a KD alters food cravings such that adherents consume more nutrient-dense foods on a regular basis. More research is needed to determine how these changes in food cravings may affect outcomes in cancer patients.
This study has several strengths. This investigation was part of the first randomized, controlled trial examining KDs in the context of cancer. In addition, to our knowledge this is the first study to examine KD’s effects on quality of life in women with ovarian or endometrial cancer. Our results are limited by the heterogeneous nature of the sample in that approximately 25% of the participants received concurrent chemotherapy while on their assigned diets. As stated previously, in all likelihood, the administration of the questionnaires only in a fasted state influenced the results reported here. Finally, although this trial is one of the largest conducted to date in this field, it is limited by a relatively small sample size, which was sufficient to detect only large between-group differences; larger studies are needed.
In conclusion, we found that, among women with ovarian or endometrial cancer, a KD does not diminish quality of life; indeed, it may improve physical function, increase energy, and diminish specific food cravings. These findings may generalize to other cancers associated with obesity, such as colorectal or post-menopausal breast cancers. However, further research is needed to determine for which cancer types and treatment regimens a KD may be most appropriate and to examine how a long-term KD may impact the lived experience of cancer patients.