Review: Ketogenic diet in the treatment of cancer – Where do we stand? 評論：生酮飲食治療癌症-我們的立場是什麼？

3.3. Clinical evidence

For many types of cancers, the combination of surgery, radiation, and chemotherapy is the gold standard of care [68]. However, in highly aggressive cancer types with poor prognosis, for example triple negative breast cancer, no effective standard therapy is available [69]. Hence, new approaches that enhance therapeutic efficacy are urgently needed. As indicated by preclinical evidence, the KD represents a novel therapeutic approach for certain types of cancers (Table 1). Our aim was to summarize and critically evaluate human studies examining KDs in the context of cancer (Table 2). Most of the presented data are from case reports [8], [69], [70], [71], [72], [73], [74], [75], [76], [77] or pilot/feasibility studies [52], [55], [78], [79], [80], [81], [82], [83] mostly focusing on safety and tolerability of the KD. Only one randomized controlled trial is available to date [84], [85]. Nevertheless, consistent findings include a moderate reduction of blood glucose levels, induction of ketosis, feasibility and tolerability of the KD as well as improvement in quality of life (Table 2). Moreover, and very importantly, none of the studies reported any serious adverse events or toxicity related to the KD (Table 2), supporting the safety of a KD intervention.

Despite the lack of randomized controlled trials with large patient cohorts, several individual observations that support the antitumor effects of KDs have been reported in humans (Table 2). For example, an excellent therapeutic response to a KD was noted in two pediatric patients with advanced-stage malignant astrocytoma. The diet was administered either after or in combination with standard therapy [74]. After eight weeks of KD, positron-emission tomography revealed an average decrease of 21.8% in glucose up-take at the tumor site in both children. One of the children exhibited significant improvement in mood and skill learning and continued the KD for twelve months, remaining free of disease progression. Both patients remained in remission for five and four years after diagnosis, respectively, with good quality of life. In a second example, a women with triple-negative breast cancer who received a combination of KD with metabolically supported chemotherapy, hyperthermia, and hyperbaric oxygen showed a complete clinical, radiological, and pathological response [69]. Moreover, a prospective feasibility trial applying the MAD to patients with advanced malignancies who were not receiving chemotherapy reported that four patients were stable or improved after sixteen weeks of dietary intervention [78]. Interestingly, among these four patients, three were diagnosed with melanoma. All three continued the MAD beyond sixteen weeks and significantly exceeded their expected lifespan, which is usually only three months. Furthermore, a study in recurrent glioblastoma patients investigated the effect of a KD in combination with intranasal perillyl alcohol [20]. After three months of combined therapy, the partial response rate was 77.8% and 25% in the KD and the control group, respectively. Moreover, 50% of patients in the control group showed progression of the tumor compared to 11.1% in the KD group. In contrast, other studies could not support the potential tumor suppressive effect of the KD (Table 2). For example, a retrospective analysis of tumor images of five patients with tuberous sclerosis complex (TSC) receiving a 3–4:1 KD for seizure control revealed no significant effect of the KD on the growth suppression of TSC-related tumors [82].

Besides direct effects on tumor growth, the KD has the potential to improve the overall health status of patients as well as quality of life. Thus, some studies reported an overall normalization or improvement of lipid profiles, including reduction of total cholesterol, LDL, and HDL cholesterol, in cancer patients on a KD [20], [79], [86]. Furthermore, the KD significantly reduced insulin levels, and an inverse association between BHB and insulin-like growth factor 1 (IGF-1) concentrations was described [85]. In two insulin-dependent diabetic cancer patients, insulin requirements decreased by 75% [79] and 100% [78], respectively. A liver biopsy of a patient with an intra-abdominal desmoid tumor receiving lipid-based total parenteral nutrition for five months did not reveal lipid accumulation within the liver. Regarding quality of life, stable quality of life to significant improvements have been described for several cancer patients consuming a KD [8], [69], [74], [78], [79], [80], [84]. Moreover, a study investigating the effects of a KD on physical function, perceived energy and food cravings in ovarian and endometrial cancer patients reported overall improved physical health and increased energy in women on a KD without chemotherapy [84]. The authors stated that the latter effect could be related to the less advanced disease stage of the patients not undergoing chemotherapy.

Overall, most studies reported a reduction of body weight in patients who adhered to the diet (Table 2). In this regard it has been shown that the KD reduced total fat mass but was sufficient to preserve lean mass [8], [85], [87], [88]. In cachectic patients, however, the KD induced weight gain, and patients maintained a positive nitrogen balance [70]. In malnourished pediatric patients, the KD was designed specifically to induce weight gain, and the children showed weight stabilization and improved nutrient and caloric intake [74].

The reason why some studies could not draw any conclusion regarding the efficacy of the KD in cancer patients was either due to a lack of power of the study or due to low adherence of cancer patients to the diet regime (Table 2). In most cases, however, low adherence was attributed to either poor tolerability of the KD associated with nausea, fatigue, or constipation or because patients stopped the diet because of tumor progression. Poor tolerability has been reported, for example, in a study with lung and pancreatic cancer patients because of suboptimal compliance to a 4:1 KD [55]. One patient experienced asymptomatic grade 4 hyperuricemia, and another patient experienced grade 3 dehydration. That study was seeking a therapeutic response and, therefore, was very strict in achieving compliance to a high ratio KD. Based on our experience and as shown in several studies (Table 2), stable ketosis can also be achieved in most patients with a KD 2:1, indicating that a 4:1 KD as used for therapy-resistant epilepsy might not be necessary in cancer patients. Klement et al. suggested three measures that could help to maximize compliance and ketosis: 1) frequent support by an experienced dietitian, 2) provision of KD formulas and meals, and 3) offering cooking classes [8]. Furthermore, to support compliance to the KD, strong commitment and cooperation from both the patient and his/her family are necessary to maintain dietary-induced ketosis. Side effects, such as micronutrient deficiencies, appetite loss, nausea, headaches, light-headedness, constipation, fatigue, hyperlipidemia, reduced vision, and weight loss, could be avoided or reduced when the KD is initiated slowly and adequately supplemented with vitamins and minerals [8], [44]. Potential adverse effects of the long-term use of KDs, as for example gastrointestinal pain or renal stones [89], are generally mild, associated more with MCT oils, and can be reduced if the KD is consumed in restricted amounts/restricted time frames of radiochemotherapy [8], [77]. Nevertheless, several studies report good tolerability of the KD in patients who adhere to the diet [8], [20], [52], [69], [70], [71], [73], [74], [77], [78], [79], [80], [83], [90], and the authors mostly concluded that the use of a KD in cancer patients is feasible and safe [8], [52], [73], [76], [78], [79], [80], [81], [84], [87], [88], [90], [91].