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Tan-Shalaby et al.
Nutrition & Metabolism (2016) 13:52 Page 10 of 12
was uniformly Caucasian male even though we did not rather than fat metabolism. Increased leptin levels are
exclude diverse racial types nor exclude females. Had we associated with faster tumor growth in animal studies
expanded our trial to another year’s length we perhaps [27]. In humans, particularly obese individuals have
could have attracted a more diverse patient sample. higher leptin levels and correspondingly have higher
One previous study had recruited patients from different rates of human cancers. A study of melanoma patients
institutions each with their own dietician, hence dietary found significantly higher leptin levels in those with
instruction was not standardized across the board [4]. positive sentinel node biopsies [28]. The patients who
Blood work/scans were sent to separate laboratories responded with stable or improved disease lost more
and imaging facilities, possibly causing variations in percentage weight, and by doing so decreased the body
data interpretations. We hoped to improve on this by leptin and consequently slowed down angiogenesis.
recruiting all our subjects from a single institution and The effect of the diet on lifespan cannot be adequately
uniformly obtained all our testing from our inpatient examined here due to the low number of subjects en-
hospital laboratory. Our images were read by a dedicated rolled and the diverse nature of each patient’s individual
nuclear radiologist as well as obtained via the same dedi- tumors. However out of the four patients who did well
cated PET/ CT scanner. Travel time was also an issue. until 16 weeks, three had a diagnosis of melanoma and
Most of our patients lived a long distance from our hos- all three not only went beyond 16 weeks of dieting but
pital (some > 3 h away) which made recruitment difficult also significantly exceeded their expected lifespans
given the travel time and frequency of visits. Majority of (typically only 3 months). One remains alive and free
the interested patients who lived locally did not qualify, as of disease at 121 weeks. Due to variations in timing of
they were not US veterans, one reason for inclusion. blood draws, the reported ketone levels of these patients
We chose to scan with PET/CT imaging as early as were not significantly elevated and none achieved the
4 weeks. Previous studies show that PET/CT scans can target glucose ketone index, although two did report
detect partial responses to chemotherapy as early as after significant halitosis which could mean that their re-
one cycle [2]. In the future we feel that an 8 week PET/ corded ketone levels may be underestimating their true
CT scan instead of four will be more useful as some tu- average daily [20, 21] Whether patients with malignant
mors may actually be experiencing a tumor flare prior to melanomas have intrinsic characteristics making them
shrinkage. We also excluded patients with brain metasta- more responsive to the ketogenic diet over other tumor
ses because we expected poorer performance statuses. In types remains to be investigated further.
hindsight it could have been better to include them. Many
of these patients actually do well enough to last through a Conclusions
short dietary course without any deleterious effects. The modified Atkins diet is well tolerated by patients
Not all of our patients responded to the KD. Previous with advanced cancer. Hematologic parameters, serum
work on identifying characteristics that would predict cholesterol, renal function and lipid levels remained
for response have studied the role of defective OXPHOS stable. There was improvement in insulin requirements
enzymes [11, 22]. The metabolic switch from oxidative and renal function in a few patients. Quality of life mea-
phosphorylation to non-oxidative fermentation is thought sures remained stable and the diet was simple to initiate
to be related to upregulation of transketolase TKTL-1 pro- and implement. For some, the adherence to the diet
tein expression which was correlated with invasive tumors remained excellent at one year and beyond. It is possible
[23, 24]. Identification of ketolytic and glycolytic enzyme that therapeutic efficacy could be greater in future stud-
overexpression in malignancies may help stratify those ies where patients can enter the predicted GKI zone. In
patients with low enzyme expression and accordingly this study, ideal target glucose and ketone values may
should respond more favorably to the KD [11, 24]. have been reached but were not accurately recorded due
Most of our patients were overweight and were likely to variations in patient compliance with blood draw tim-
to be leptin resistant and as a result have high body leptin ing and fasting states. The diet might help improve quality
levels. Leptin is a pro-angiogenic metabolic hormone and of life and enhance tumor response to chemotherapy
which is secreted by adipose tissue. It sends satiety signals in cancer patients. Looking forward, the incorporation of
to the hypothalamus in response to caloric intake. Ghrelin immunohistochemical staining for ketolytic/glycolytic
is the opposing hormone which increases our appetite. In- enzymes and biomarkers (i.e. leptin, insulin) and their
take of sucrose during the fasting state results in a rise in role in tailoring metabolic cancer management merits
serum leptin. However, over consumption of foods high in further study. Notably, melanoma patients represented
sucrose leads to a blunted leptin response, which leads to the three who benefitted most from this study. Future
higher serum leptin levels [25, 26]. Unlike leptin, ghrelin studies should investigate the modified Atkins diet
secretion is suppressed by intake of both sucrose and fats. MAD or the ketogenic diet KD and their potential benefits
Leptin secretion is therefore probably linked to sucrose to this type of cancer.

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Tan-Shalaby et al.

Nutrition & Metabolism (2016) 13:52 Page 10 of 12

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