Table 1 Ketogenic diet results table

Cohen, 2016, USA [21]

Feasibility RCT

73 randomised, 45 analysed (25 in IG, 20 in CG)

Mean age 60.2y (range 31-79y)

Recurrent ovarian cancer

KD: 5% CHO, 25% protein, 70% fat over 12 wks.

Usual care (24% received concurrent chemotherapy)

62% retention

80% adherence (defined as ∼0.5 mmol/L urinary ketone conc.)

↔ lean body mass between groups

↓total body fat (kg) (32.7 ± 3.1 vs 41.2 ± 4.4) android fat (kg) (2.8 ± 0.4 vs 3.6 ± 0.5), and visceral fat (g) (975 ± 150.9 vs 1024 ± 175.6) (p < 0.05) in IG

↓insulin (μU/mL) in IG (6.7 ± 0.9 vs 12.1 ± 1.5, p < 0.01)

↔ glucose

↓C-peptide in IG (2.0 ± 0.3 vs 3.0 ± 0.3, P < 0.01)

↔ IGF-I or IGFBP-1

↑ physical component scores in IG (45 vs 40 p = 0.04)

↔ mental component score

↑cravings for salt (p = 0.03), and

↓cravings for starchy foods (p = 0.03) and fast food fats (p = 0.04) in IG

↔ cravings for high-fat foods or sweets

Anderson 2016, USA [22]

Phase 1 trial with single assignment

9

Age NR

Stage 3-4b head and neck squamous cell carcinoma

4:1* KD fed by PEG followed by oral intake for 5 wks.

Concurrent platinum chemo-radiotherapy

33% retention

Ppts who discontinued completed a median of 6 days (range 0–8 days) on KD

Trial terminated early (intended sample size 14)

6 discontinued: additional stress (n = 1), grade 2/3 nausea (n = 3), grade 3 fatigue (n = 1), grade 4 hyperuricemia (n = 1)

2 SAEs: hyperuricemia, pancreatitis

4 SAEs: parotiditis, nausea, vomiting, neutropenic fever

↑Ketones in compliant ppts (median 24 days, range 19–25 days)

↑BHB levels in compliant ppts (median 5 wks, range 4-5wks)

↔ lipid panel test at 3wks

↑ Serum oxidative stress markers with increasing days on KD

Renda 2015 and Dardis, 2017, USA [23]

Phase 1/2 trial with single assignment

14

Mean age 45y (range 37-63y)

Brain cancer

4:1 KD* for 8 wks during concurrent radiation and chemotherapy, followed by a 1:1 diet during adjuvant temozolomide chemotherapy

47% recruitment

14% stopped due to tolerability

Trial terminated early (intended sample size 40)

No weight loss > 10% of baseline (NB - only reported in preliminary results from 6 ppts)

29% reported nausea

Rieger 2010 and Rieger, [24], Germany [25]

Pilot study with single assignment

20

Mean age 55y (range 30-72y)

Brain cancer

KD: < 60 g/day CHO consumed with 500 ml highly fermented yoghurt drinks and 2 plant oils daily.

Followed diet for 6–8 wks alone and for a further 6–8 wks either alone or during salvage chemotherapy (n = 8)

15% discontinued after 2–3 wks (diet negatively affecting QoL)

↓ body weight (− 2.2%) at 6–8 wks

No SAEs attributable to diet

No grade 3 AEs

12 out of 13 evaluable ppts achieved ketosis (73% of urine samples had detectable ketosis)

↔ blood glucose and HbA1c at 6–8 wks

Zahra, 2017, USA [26]

Phase 1 trial with single assignment

9

Age range 51-83y

Non small cell lung cancer (n = 7)

Pancreatic cancer (n = 2)

4:1 KD: 90% fat, 8% protein,2% CHO (KetoCal powder + food provided). KD 2 days prior to chemo-radiotherapy until end of treatment (6wks for lung and 5wks for pancreatic)

71% withdrawal in lung cancer ppts: Difficulty complying (n = 4), grade 4 hyperuricemia (n = 1)

50% withdrawal in pancreatic cancer ppts: Grade 3 dehydration (n = 1)

Average time on diet: 16.9 days (0–42) for lung and 21 days (8–34) for pancreatic cancer ppts

↓body weight in lung (−6%) and pancreatic (−9.75%) cancer ppts

Grade 3/4 nausea (n = 1), dehydration (n = 1), esophagitis (n = 1)

Ketosis achieved in 89%

Ketosis maintained in 33%

↔ blood glucose

↑ median plasma protein carbonyl content (nmol/mg) from pre- to post- diet (1.0 vs ≈ 1.4, p < 0.05)

Artzi, 2017, Israel [27]

Non randomised trial

9 (5 in IG, 4 in CG)

IG: mean age 51y (range 37–69y)

CG: mean age 46y (range 27–64y)

Brain cancer

4:1 KD using KetoCal® formula for 2–31 months

Bevacizumab, temozolomide or rindopepimut

40% adherence (self-report and urine ketones; ppt considered adherent when ketone level was > 2 urine ketosis)

80% tolerance (tolerability criteria not defined)

Evidence of ketone bodies within the brain found in 67% of cases and 0% of controls

Champ, 2014, USA [28]

Retrospective case control study

53 (6 cases, 47 controls)

Mean age 54y (range 34-62y)

Grade 3–4 glioblastoma

“Patient driven KD” – CHO levels below 50 g/day or 30 g/day if ketosis not reached

Chemo-radiotherapy or adjuvant chemotherapy

NR

Grade 1 constipation (n = 2)

Grade 2 fatigue (n = 1)

No grade 3 toxicity

Confirmed ketosis in all cases

↓mean glucose in cases from 142.5 mg/dl (range 82–181 mg/dl) to 84 mg/dl (range 76–93 mg/dl) (p = 0.02)

Klement, 2016, Germany [29]

Case series

6

Mean age 60y (range 40-74y)

Breast (n = 1), prostate (n = 1), rectal (n = 3) and lung (n = 1) cancer

KD: 80% fat and < 50 g/day CHO during treatment (mean 48.2 days, range 32–73 days)

Radiotherapy or chemo-radiotherapy

100% adherence rate to < 50 g/day CHO consumption

Average energy from fat 73%

Low BHB and high glucose in some ppts self-reporting as adherent

KD more satiating than previous diet (self report)

General subjective feeling on diet rated as “good”

100% reported they would continue with a low CHO/KD after RT

↓ weight (kg/wk) in 33%

↓FM in 50%

↔ absolute FFM

↑ FFM relative to body weight in 50%

↑ (worsening) symptom scores for fatigue, nausea/vomiting, appetite loss, diarrhoea

↑ in BHB

↔ glucose

↔ global health status and total functional scores

Attar [30] and 2016, USA [31]

Retrospective review

13

Age range 23-72y (mean NR)

Recurrent brain cancer

Modified Atkins Diet: up to 60 g/day carbohydrate (2–5% total calories) from 1 to 21 months

9 on chemotherapy

85% adherence (range 1–21 months)

2 discontinued: weight loss (n = 1), inconvenience (n = 1)

1 SAE: renal calculus at 11 months

100% achieved ketosis

Randazzo, 2015, USA [32]

Retrospective data registry review

596 (81 cases, 515 controls)

Mean age 49.6y (range NR)

Brain cancer

Self-administered “special diets” including KD, Low CHO, vegetarian/vegan

Usual care

NR

NR

NR – data not stratified by diet type