Is There a Role for Carbohydrate Restriction in the Treatment and Prevention of Cancer?

Rainer J Klement; Ulrike Kämmerer

Disclosures

Nutr Metab. 2011;8(75) 

In This Article

The Benefits of Mild Ketosis

The study of Breitkreuz et al. shows that ketosis might not be necessary to improve the cachectic state of cancer patients. In recent years, however, more evidence has emerged from both animal and laboratory studies indicating that cancer patients could benefit further from a very low CHO KD. In their mouse models, Tisdale et al. already noted that the KD not only attenuated the cachectic effects of the tumor, but also that the tumors grew more slowly (although they did not attribute this to a direct anti-tumor effect of β-hydroxybutyrate). Tumor growth inhibition through a KD has now been established in many animal models, is supported by a few clinical case reports, and laboratory studies have begun to reveal the underlying molecular mechanisms.

In vitro Studies

More than 30 years ago, Magee et al. were the first to show that treating transformed cells with various, albeit supra-physiological, concentrations of β-hydroxybutyrate causes a dose-dependent and reversible inhibition of cell proliferation.[116] Their interpretation of the results that ''…ketone bodies interfere with either glucose entry or glucose metabolism…'' has been confirmed and further specified by Fine et al., who connected the inhibition of glycolysis in the presence of abundant ketone bodies to the overexpression of uncoupling protein-2 (UCP-2), a mitochondrial defect occurring in many tumor cells.[127] In normal cells, abundant acetyl-CoA and citrate from the breakdown of fatty acids and ketone bodies would inhibit key enzymes of glycolysis to ensure stable ATP levels; in tumor cells, however, the same phenomenon would imply a decrease in ATP production if the compensatory ATP production in the mitochondria was impaired. For several colon and breast cancer cell lines, Fine et al. showed that the amount of ATP loss under treatment with acetoacetate was related to the level of UCP-2 expression.

Very recently, Maurer et al. demonstrated that glioma cells - although not negatively influenced by β-hydroxybutyrate - are not able to use this ketone body as a substitute for glucose when starved of the latter, contrary to benign neuronal cells.[128] This supports the hypothesis that under low glucose concentrations, ketone bodies could serve benign cells as a substitute for metabolic demands while offering no such benefit to malign cells.

Animal Studies

To our knowledge, the first and - with a total of 303 rats and nine experiments - most extensive study of a KD in animals was conducted by van Ness van Alstyne and Beebe in 1913.[129] Experiments were divided into two classes: in the first class, rats in the treatment arm were fed a CHO-free diet consisting of casein and lard for several weeks before plantation of a Buffalo sarcoma, while the control arm received either bread only or casein, lard and lactose. Rats on the CHO-free diet not only gained more weight than the controls, but also exhibited much less tumor growth and mortality rates, the differences being "… so striking as to leave no room for doubt that the diet was an important factor in enabling the rats to resist the tumor after growth had started." In a second class of experiments using either the slow-growing Jensen sarcoma or the aggressive Buffalo sarcoma, the rats were put on the CHO-free diet on the same day that the tumor was planted. This time, differences between the treatment and control groups were "… so slight that … one is left in no doubt of the ineffectiveness of non-carbohydrate feeding begun at the time of tumor implantation." Interestingly, this parallels the observation of Fearon et al. that rats who started to receive a KD at the same day as tumor transplantation did not differ from controls in either body or tumor weight after 14 d.[120] In these rats, it was noted that despite persistent ketosis, blood glucose levels were not significantly lower than in controls which were also fed ad libitum. This stability of blood glucose, independent of ketosis, was subsequently confirmed in studies in which mice were fed ad libitum on a KD[84,114,121–123,130] although two studies reported a drop in blood glucose concentrations compared with the control group.[116,131] In the study of Magee et al., however, diet was presented as a liquid vegetable oil and energy intake was not monitored, allowing for the possibility that the animals underate voluntarily, in this way consuming a "caloric restricted KD" used in several experimental settings from the Seyfried lab,[84,114,132] which was shown therein to be superior to the unrestricted KD in tumor growth control. That "caloric restriction" per se can hamper tumor growth has been impressively demonstrated already in 1942 by A. Tannenbaum in a series of comprehensive mouse models with different mouse strains and tumor induction types.[133] Throughout all experimental series, a strict restriction of food intake (impeding weight gain) several weeks before inducing tumorigenesis by application of 3,4 benzpyrene decreased the appearance rate and appearance time of tumors in the diet mice compared to the ad libitum controls. Notably, the calorierestricted diet was composed of 53% CHOs compared to 69% in the control group. Despite a lack of data on blood glucose and ketone body levels, it could be speculated that the strict restriction of food per se (to 50–60% of the control group) induced a ketotic state and thus the ketones were - at least to some extend - responsible for the effects observed.

In Table 1, we summarize the main results of various mouse studies that determined the effects of KDs on tumor growth and host survival. The results seem to indicate an anti-tumor effect of ketosis. Freedland et al. indeed reported that the mice with the highest levels of ketone bodies had the longest survival times in a human prostate cancer xenograft model.[134] But other studies suggest that there are further possible factors to consider. Seyfried et al. used linear regression to show that plasma glucose and IGF1 levels are a better predictor of tumor growth than ketone bodies in a murine astrocytoma model.[84] Tumor growth in this as well as in a follow-up[114] study was only retarded when the KD had been restricted to induce body weight loss, again underlining the effect of caloric restriction per se. This contrasts with other studies showing growth-inhibitory effects of unrestricted or higher-caloric KDs despite neither decreases in blood glucose concentration nor body weight loss compared with a control group.[130,134,135] According to Otto et al., whose diet had been enriched in MCT and omega-3 fatty acids, fat quality might play a role in explaining these results.[130] The situation in humans might be different as well, as for example Fine et al. found no correlation between calorie intake or weight loss and disease progression in ten patients on an unrestricted KD[136] (see also below).

Concerning fat quality, Freedland et al. observed that a diet rich in corn oil might stimulate prostate cancer growth to a greater extent than one rich in saturated fat.[134] A recent study suggests, however, that tumor growth inhibition neither depends on fat quality nor ketone body levels.[131] In this case, mice injected with either murine squamous cell carcinoma or human colorectal carcinoma cells received a low CHO, high-protein diet in which ~ 60 E% was derived from protein, 10–15 E% from CHO and ~ 25 E% from fat. No systemic ketosis was measured, yet tumors grew significantly less compared with a standard diet containing 55 E% from CHO and 22 E% from the same fat source. IGF1 levels and body weight remained stable, so these findings could not be attributed to one of these factors. There was, however, a significant drop in blood glucose, insulin and lactate levels, and a positive correlation between blood lactate as well as insulin levels and tumor growth was found. The study of Venkateskwaran et al. indicates that in prostate cancer insulin and/or IGF1 play major roles in driving tumor cell proliferation.[97]

The diversity of these findings should not be surprising, given the variety of mice strains, tumor cell lines, diet composition and time of diet initiation relative to tumor planting. Instead, it seems remarkable that the same basic treatment, namely drastic restriction of CHOs, apparently induces anti-tumoral effects via different pathways. Thus, it may depend on the circumstances which variables - including blood glucose, insulin, lactate, IGF1, fat quality and ketone bodies - are the best predictors of and responsible for the anti-tumor effects of very low CHO diets.

Human Studies

Until now, no randomized controlled trials have been conducted to evaluate the effects of a KD on tumor growth and patient survival. It has to be noted in general, however, that any dietary intervention requiring a dramatic change of life style makes randomized studies nearly impossible - however, even prospective cohort studies are missing. There is only anecdotal evidence that such a diet might be effective as a supportive treatment. One study investigated whether a high-fat diet (80% non-nitrogenous calories from fat) would inhibit tumor cell replication compared to a high-dextrose diet (100% non-nitrogenous calories from dextrose) in 27 patients with gastro-intestinal cancers.[137] Diets were administered parenterally and cell proliferation assessed using thymidine labeling index on tumor samples. After 14 days, the authors found a non-significant trend for impaired proliferation in the high-fat group. Whether ketosis was achieved with this regime was not evaluated, but blood glucose levels were comparable in both trial groups. A very recent pilot trial demonstrated the feasibility of a low CHO up to a ketogenic regimen implemented for 12 weeks in very advanced outpatient cancer patients. Notably, severe side effects were not observed, nearly all standard blood parameters improved and some measures of quality of life changed for the better.[138] The first attempt to treat cancer patients with a long-term controlled KD was reported by L. Nebeling in 1995 for two pediatric patients with astrocytoma.[139] The results of those two cases were very encouraging and the diet was described in detail in another publication.[140] Implementing a KD with additional calorie restriction in a female patient with glioblastoma multiforme clearly demonstrated that this intervention was able to stop tumor growth.[132] This was achieved, however, on the expense of a dramatic weigh loss of 20% over the intervention period, which is no option for the majority of metastatic cancer patients being in a catabolic state. A first clinical study applying a non-restricted KD for patients with glioblastoma (ERGO-study, NHI registration number NCT00575146), which was presented at the 2010 ASCO meeting,[141] showed good feasibility and suggested some anti-tumor activity. The protocol of another clinical interventional trial (RECHARGE trial, NCT00444054) treating patients with metastatic cancer by a very low CHO diet was published in 2008,[142] and preliminary data from this study presented at the 2011 ASCO-meeting showed a clear correlation between disease stability or partial remission and high ketosis, independent of weight loss and unconscious caloric restriction of the patients.[136] While a randomized study for the treatment of prostate cancer patents applying the Atkins diet (NCT00932672) is currently recruiting patients at the Duke University, another trial posted at the clinical trials database (ClinicalTrials. gov) is not yet open for recruitment (NCT01092247). Very recently, two Phase I studies applying a ketogenic diet based on KetoCal® 4:1 started recruitment at the University of Iowa, intended to treat prostate cancer patients (KETOPAN, NCT01419483) and non-small cell lung cancer (KETOLUNG, NCT01419587). Thus, in the future, several data should be available to judge whether this kind of nutrition is useful as either a supportive or even therapeutic treatment option for cancer patients.

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