Ketogenic diets as an adjuvant therapy for glioblastoma (KEATING): a randomized, mixed methods, feasibility study

Glioblastoma (GBM) is the commonest malignant primary brain tumor in adults, affecting 2–3 per 100,000 per year [1]. Even with maximal safe resection, radiotherapy and temozolomide [2, 3], the prognosis remains poor [4]. In the last 10 years, a series of large-scale clinical trials testing targeted therapies have all reported negative results [4‐6] with no change in the current standard of care. Patients and caregivers often explore other alternative treatment options, including dietary changes such as the ketogenic diet (KD). Indeed, the James Lind Alliance Priority Setting Partnership identified that ‘the effect of lifestyle factors, including diet, on tumor growth’ to be a top 10 research priority for the neuro-oncology community [5].

KD is an ‘umbrella term’ used to describe high fat, low carbohydrate, adequate protein diets which promote the utilization of fat for energy, in the form of ketones. Initially hypothesized to work by exploiting the ‘Warburg effect’ [6‐9], newer theories have proposed other mechanisms of action, with ketone bodies and medium chain triglyceride (MCT) fats playing a role in tumor metabolism, rather than or in addition to a reduction in glucose [10‐13]. Animal models of glioma have shown that KD potentiates the effects of radiotherapy [14], reduce peri-tumoral edema [15] and reduce tumor angiogenesis [7]. In patients with gliomas, the evidence for KD is limited to case studies and single case reports [16‐22]; all utilizing different KDs at different time points in the treatment pathway. No studies have been powered to assess efficacy.

Prior to designing and undertaking an adequately powered randomized control trial (RCT) investigating the efficacy of KDs in the therapeutic management of GBM, feasibility must be demonstrated [23‐25]. We conducted the KEATING study to i) investigate protocol feasibility; ii) explore the potential impact of the study on patients’ quality of life and health; iii) explore patients’ perspectives of their decision-making when invited to participate in the study; and iv) optimize future phase III clinical trial design, whilst comparing two different KDs in an NHS setting.

This randomized, pilot study with an embedded qualitative design was designed to explore the feasibility of KD trials for patients with glioblastoma, with a view to recommending improvements to optimize the design of future phase III trials.

KEATING recruited to time and target, despite an initial slow start. The recruitment rate (28.6% of the eligible population) was much lower than NIHR HTA funded oncology clinical trials (50 to 89%) [33], but in keeping with recent survey data from the National Brain Tumour Society, with 21% of patients with brain tumors participating in clinical trials [40, 41]. Screening log data at the start of KEATING revealed that patients were declining to participate due to (i) not wanting to participate in research; (ii) the burden of dietitian visits; and (iii) the burden of KD. During the qualitative study those patients who declined to participate in KEATING identified their quality of life as an important factor in decision-making, and this aspect was not detected in the screening log data or in previous surveys regarding participation barriers [40]. These patients also spoke of the role of caregivers in influencing their decision to participate or not in KEATING, an aspect highlighted in trials elsewhere [41]. In contrast, patients who consented to KEATING made an intuitive and emotional decision, later reflecting that this decision was based upon quantity rather than quality of life. This optimism surrounding longevity of life is often used as a coping strategy by patients and may not invalidate their informed consent. There is currently little guidance offered by the Health Research Authority (HRA) Good Clinical Practice guidelines [42] regarding this matter, thus clinicians should continue to use their clinical judgement when assessing patients’ informed consent to participate in trials. Our findings are in keeping with recent publications highlighting the need for improved recruitment strategies and decisional support in neuro-oncology populations [40, 41].

The retention rate in KEATING was lower than anticipated. Out of the 12 patients randomized, 10 commenced KD and only four met the primary endpoint of three-month dietary intervention (1 KD, 3 MKD). Cancer trials in general report median retention rates of 89% (IQR 79–97% with valid primary outcome data at follow up) [33] and previous KD studies for patients with GBM report retention rates of 50 to 100%, with retention determined at eight weeks [19], three months [18, 32] and the point of tumor progression [17]. However, patients in these previous KD studies self-selected to try the diet, mainly at recurrence or post-treatment, creating an optimistic bias in retention, when compared to the general unselected GBM population approached for KEATING. Those who withdrew from KEATING did so either after randomization but prior to commencing the diet (n = 2) or after following the KD for approximately six weeks (MCTKD median 38 days [36 to 40 days], n = 2); MKD 39.5 days [32 to 49 days], n = 4), during which time patients were undergoing radiotherapy and concomitant temozolomide chemotherapy. Patients reported their reasons for withdrawal to be related to dietary burden and side effects, in particular nausea, which could have been related to the chemotherapy. Those continued on their assigned KD were generally younger patients with more favorable prognostic features (MGMT methylated; IDH-1 mutant) and this may also have influenced their ability to stay on the study and implement the diet.

The reasons for poor retention on diet were explored in our qualitative study. Those who withdrew spoke of finding their low urinary and blood ketones to be ‘demoralizing’, feeling that the diet was not working, and withdrawing due to the negative effect this feeling had on their quality of life. This was confirmed in the quality of life data as patients who withdrew reported their global health status (GHS) to be below the brain cancer reference value at week six of the study. We appreciate multiple factors can affect the quality of life for these patients and whilst ketones are used to monitor the diet, urinary ketones not always robust markers of compliance and can be effected by hydration levels and the use of dexamethasone. Therefore low ketones may demoralize patients, even when they appear to be following the diet robustly.

For those patients who continued to participate in the trial to 12 months, GHS reduced within the MCTKD group and improved in the MKD group. However, during the qualitative interviews, both groups reported to experiencing a ‘fantastic quality of life’ describing the diet as offering a sense of ‘control’ whilst receiving their tumor treatment. Although the EORTC QLQC30 and BN20 questionnaires are validated for patients with glioblastoma, they are time consuming to complete and some questions are not relevant for patients following KDs. It may be beneficial for future KD trials to reduce the length of the questionnaire and therefore patient burden, focusing particularly on GHS, as these questions provided the most insight in KEATING.

During interviews, patients reported several motivational factors for continuing with the diet, including through online blogs of long term glioblastoma survivors, positive MRI results and high ketone levels, using these as a means of validating their decision to stay on diet. This corroborates the findings from KEATING since high ketones indicted compliance with KD. Patients with higher ketones stayed in the study, whilst those with lower ketones withdrew early, at around week six. Furthermore, a pilot study for KD in patients with other advanced cancers (breast, ovarian, lung, gastrointestinal), also experienced similar retention rates to KEATING (retention rate 31%, n = 5 of 16), in a trial which permitted a more liberal KD (70 g of carbohydrates per day) and where all food provision was provided [43]. Thus, a more flexible dietary approach may not be the simple solution.

The high withdrawal rates in KEATING suggest that a three-month KD intervention may be too long for most patients. Our qualitative study also highlighted that those who withdrew considered the three-month intervention to be undesirable, an opinion also reflected by those who declined, further corroborating findings from KEATING. A shorter, six-week intervention, is likely to be more tolerable and acceptable to patients. This could be offered alongside radiotherapy and concomitant chemotherapy, which coincides with the proposed optimal time for the diet derived from animal model data [14]. Offering the diet at the same hospital site as the radiotherapy would aid a timely start of the diet. Whilst patients reported ‘feeling free again’ once the diet was discontinued, it is important to note, that this may not necessarily equate to dietary acceptability outside of a clinical trial. In a future post-trial environment, information regarding the efficacy of the diet may be available, which could alter patients’ willingness to engage.

The qualitative study also highlighted caregivers to be key in supporting patients to implement the diet. The role of caregivers, both in the decision-making of patients and the ongoing support offered, were aspects that were underappreciated in KEATING. A recent KD study for patients with Alzheimer’s disease, also highlighted dietary and caregiver burden to be influential over patient withdrawal [44].

KEATING had several limitations. The return rate of food and ketone diaries was low at 12 months, subsequently affecting the analysis. This is a common problem in dietary intervention trials, given the time commitment required to return diaries. All accounts of dietary intake were also self-reported and at risk of reporter bias. The sample size for the qualitative was small and we cannot be certain that saturation was achieved. Nevertheless, drawing on the concept of ‘information power’ in qualitative research [36], this study had a well specified aim, and it has provided insights that will be valuable in informing a future phase III trial. Some patients were also interviewed up to three months after their decision about KEATING. They may have found it difficult to accurately recall their decision-making process, particularly given the nature of their condition and the numerous other decisions they will likely have had to make regarding their care and treatment.

In order to optimize protocol feasibility and patient experience future trials should consider the following suggestions:

In conclusion, recruitment of patients with GBM to a KD trial is possible. To assess efficacy in a phase III clinical trial, a six-week intervention period is proposed. The role of caregivers in the patients’ decision-making process and in supporting patients to implement KDs should not be underestimated.