The systematic search revealed 19.205 results. Six studies were added by hand search. At first, duplicates were removed leaving 16.373 studies. After screening title and abstract, 48 studies remained to complete review. Finally, 45 publications were analyzed in this review, including 5 SR, 1 review and additionally 5 publications on 3 RCTs, 2 controlled studies and 33 single-arm studies and case reports, presented in 32 publications. All in all, 765 patients were described in 39 publications.
Characteristics of included studies
Concerning the RCTs and CTs, 322 patients were included and 250 of them were analyzed, due to 72 drop-outs. The mean age of patients (only reported in 3 studies) ranged from 44.8 to 66.3 years and the range of age from 38 to 76 years (reported in 1 study). One publication only reported the median age, which was 72 years. A total of 156 (62%) participants were female and 94 (38%) were male. Concerning the studies with a fixed duration of intervention, the extent of the diet ranged from 3 to 6 months.
In the single-arm studies and case series, a total of 443 patients were included and analyzed. The age of the included patients ranged from 3 to 92 years. Information about the gender of the included patients could be obtained for 370 of the 443 patients. Out of these 370 participants, 184 (50%) were female and 186 (50%) were male. Duration of the dietary intervention in these studies reached from a single, 3 h long, application of parenteral nutrition [20] to a single case with more than 31 months of oral KD [21].
The KDs prescribed in the included studies varied extensively between studies (see Table 6 for details concerning the prescribed diets) were in most articles not described in adequate detail, and the majority did not utilize standardized dietary protocols. Furthermore, the methods used for assessing ketone body levels and diet compliance varied widely, with some studies not measuring them at all.
Excluded studies
A list of the studies excluded after full-text screening and the reasons for exclusion are presented in online resource 2.
Risk of bias in included studies
The methodical quality of the included RCTs and CTs was rated according to the SIGN checklists [18], and the results are presented in Table 2. Other study types were analyzed based on the Cochrane Risk of Bias tool [22], with the results presented in Table 3. These studies were further rated based on the Oxford criteria. These results and additional comments on methodology are provided in Table 4.
Table 2 Risk of bias in the included RCTs and CTs according to the SIGN checklist Table 3 Risk of bias in the included single-arm studies and case reports according to the Cochrane risk of bias tool Table 4 Risk of bias in the included single-arm studies and case reports rated with the Oxford criteria Efficacy of the ketogenic diet
The study characteristics and all relevant results reported in the included RCTs and CTs are presented in Table 5. Similar information concerning the included single-arm studies and case reports is presented in Table 6.
Table 5 Study characteristics and outcomes reported in the included RCTs and CTs Table 6 study characteristics and outcomes reported in the included single-arm studies and case reports Survival and disease progression
Results from RCTs and CTs
Overall survival was only analyzed in one RCT [23]. In this study, the overall survival (OS) for a subgroup of patients with neoadjuvant treatment for breast cancer was significantly higher in the intervention group (p = 0.04). However, no data for the entire study population are presented, which also consisted of patients with metastatic disease.
One RCT assessed the effects of the diet on prostate-specific antigen doubling time (PSADT) as a surrogate parameter for progression of disease [24]. Per protocol, there was no between-group difference concerning the PSADT (p = 0.446). Only in post hoc exploratory analysis with adjusting for multiple baseline covariates and proposed hemoconcentration, a significantly increased PSADT could be found.
Results from single-arm studies and case reports
Only five of these studies compared reported and expected survival, which was derived from historical controls [25,26,27,28,29]. In one study [25], two of the patients were analyzed and their survival was comparable with the expected survival, similar to another study where all of the different subgroups of patients had an OS in line with the historical controls [28]. Two other studies [26, 27] found a numerically better than expected survival. However, no statistical analysis was performed. One study, however, reported a lower-than-expected survival for the patients receiving a KD [29].
Another study compared the subgroup of patients, who received bevacizumab salvage treatment while on a KD with other patients treated with bevacizumab in the same hospital, who did not receive a KD. There was no difference in median progression-free survival (PFS) (p = 0.38) [30].
Even though most studies reported on tumor stability and progression, the results were highly heterogeneous and the tools and methods used for this assessment were only reported in a minority of them in adequate detail. Furthermore, there was no analysis for statistical significance of the findings.
An exception is the study of Fine et al. [31], which reported that patients with stable disease or partial remission on PET scan after the diet exhibited significantly higher dietary ketosis than those with progressive disease (n = 4, p = 0.018).
Feasibility and adherence
Results from RCTs and CTs
Out of the included 322 patients, which were included in the 5 studies 72 drop-outs occurred (24.7%). From the 72 drop-outs, 38 (53%) were part of the intervention group and 34 (47%) of the control group [23, 24, 32,33,34].
Results from single-arm studies and case reports
Feasibility and diet adherence was analyzed in 13 studies. In total, 84 out of 139 patients (60%) were able to continue the diet for the duration of the intervention [21, 25, 28,29,30,31, 35,36,37,38,39,40].
Quality of life
Cohen et al. used the physical component summary (PCS) and mental component summary (MCS) out of the Short Form (12) Health Survey (SF12) questionnaire to measure the quality of life (QoL) and functioning of the patients. After adjusting for baseline values and chemotherapy score, the PCS score was significantly better in the KD group. There were no significant between-group differences concerning the MCS score [32].
QoL was measured in 4 studies using the EORTC QLQ-C30 questionnaire [29, 36, 37, 41]. The results were overall inconsistent, but most often reporting stable or decreasing QoL [29, 36, 41].
Changes in body weight
Results from RCTs and CTs
All 3 RCTs reported a significant higher weight loss in the KD group than in the control group [23, 24, 42]. Freedland et al. [24] found a weight loss of 12.1 kg in the intervention group, compared to a weight loss of 0.5 kg in the control group (p < 0.001) during the 6 months of the diet. The study of Khodabakhshi et al. [23] reported a significantly larger weight loss in the intervention group than in the control group over the course of a 3 month diet with 6.3 kg compared to 1.3 kg, respectively (p < 0.001). Over the same 3-month duration Cohen et al. [42] detected a weight loss of 6.1 kg in the intervention group and 3 kg in the control group (p < 0.05).
In one of the controlled trials by Ok et al. [34], there were no significant differences in the reduction of body weight between both groups (p = 0.475). In the other trial by Klement et al. [33], only regression coefficients for the changes in body weight were provided. Here, a significantly higher reduction of body weight was reported for the subgroup of breast cancer patients (p = 0.00014) and rectal cancer patients (p = 0.01). However, in the subgroup of HNC (head and neck cancer) patients the regression coefficient for “Time × KD” implied a significant positive effect of the KD on the body weight of the patients (p = 0.008) [33].
Results from single-arm studies and case reports
Changes in bodyweight were analyzed in 15 studies. A statistical analysis to check for significance was performed in 8 studies, of which 4 found a significant reduction in bodyweight [30, 36, 37, 41]. Three of these studies found a non-significant decrease in body weight [25, 31, 43] and only Fearon et al. [44] showed a significant increase in body weight.
Out of the remaining seven studies, where no statistical analysis was performed, weight loss during the diet occurred in six studies [38, 39, 45,46,47], while only one study showed an increase in body weight [48].
One study assessed the change in BMI and reported a median decline of 1.04 kg/m2, without checking for significance [28].
Changes in body composition
Results from RCTs and CTs
Changes in body composition were analyzed in one RCT and both CTs. The RCT by Cohen et al. found a significant higher reduction of total fat mass in the KD group (− 5.2 kg) than in the control group (− 2.9 kg), while no significant differences concerning the lean body mass occurred [42].
Klement et al. provided primarily the regression coefficients for the fat mass (FM) and fat-free mass (FFM). In the subgroup of rectal cancer patients, a significantly greater loss of FM occurred in the KD group, without significant differences in FFM. A comparable result was reported in the subgroup of breast cancer patients, who experienced a significant reduction in FM, while the FFM reduction was not significant. However, the 50 kHz phase angle, an indicator for changes in cell mass, also significantly declined in the KD group. In the subgroup of HNC patients, the regression coefficients implied a significant increase in FFM in patients receiving a KD [33].
Ok et al. found a significantly lower reduction in body cell mass in the KD group (− 1.9 kg) than in the control group (− 2.9 kg), while no significant differences in body fat mass occurred [34].
Results from single-arm studies and case reports
Two studies analyzed changes in body composition [35, 41]. One study showed a significant FM reduction, without significant reduction in FFM [41], whereas the other study showed no significant effects on body composition [35].
Adverse events
Results from RCTs and CTs
Only one RCT [24] and one CT [34] monitored adverse events and only the CT by Ok et al. used a validated tool [34]. In the RCT by Freedland et al. [24], only mild AEs and one moderate AE (nausea) were reported. The number of AEs was similar at baseline but increased drastically in the KD group (30 vs 19 reported AEs) at 3 months. At 6 months, the number of AEs had subsided back to baseline in the KD group and was again close to the number in the control group at the same time.
Ok et al. [34] assessed the number of meal intake-related problems and postoperative complications. No significant differences between both groups in either of the two categories occurred.
Results from single-arm studies and case reports
Adverse events were monitored in 19 studies. A validated tool was used in 11 of the 19 studies [26,27,28,29, 31, 35, 37, 38, 45, 46]. Since many studies combined KD with standard of care (SoC) chemotherapy and/or radiation therapy, it was often not possible to determine the cause of the reported AEs. Most of the AEs were mild to moderate. The most common AEs include: fatigue [31, 45], constipation [29, 31], diarrhea [29, 35] as well as nausea and vomiting [29, 35]. Further reported AEs were: deep venous thrombosis, asymptomatic hypoglycemia, nephrolithiasis, leg cramps, dyspepsia, dry mouth, hyperuricemia, hyperlipidemia, pedal edema, anemia, neutropenia and febrile neutropenia, thrombocytopenia, halitosis, pruritus, hypoglycemia, hyperkalemia, hypokalemia, hypomagnesemia, flu-like symptoms, low carnitine, hallucinations, allergic reaction, wound infection, headaches and neuropathy [26,27,28,29,30,31, 35,36,37,38,39, 45,46,47,48,49,50].
Even though most AEs were mild to moderate, there were also DLTs (dose-limiting toxicity) like CTCAE (NCI Common Terminology Criteria for Adverse Events) grade 3 dehydration, grade 4 hyperuricemia [38] and a case of grade 5 neutropenia, resulting in the death of the patient [26].