Ketogenic Diet Therapy for Brainstem Tumors - Kuang-Lin Lin Chang Gung Children's Hospital Taoyuan, Taiwan - KETO 2018

Ketogenic Diet Therapy for
             Brainstem Tumors
6th 2018 KETO
Oct 5-9/2018
Jeju, Korea

                        Kuang-Lin Lin
                Chang Gung Children’s Hospital
                       Taoyuan, Taiwan

• Hypothesis
• Clinical data
• Cases sharing

• Based on the hypothesis that cancer cells may not be
  able to metabolize ketones as efficiently as normal
  brain cells, the ketogenic diet (KD) has been
  proposed as a complementary or alternative therapy
  for treatment of malignant gliomas.

 KD should further increase the oxidative stress in tumor cells relative to
  normal cells by limiting NADPH regeneration.
 Increased metabolic oxidative stress in cancer cells would in turn be
  predicted to selectively sensitize cancer cells to conventional radiation
  and chemotherapies.
                                                              Other mechanisms

                                     Allen et al. Redox Biology 2 (2014) 963-970

Allen et al. Redox Biology 2 (2014) 963-970

KD differentially affects
 metabolism of normal and
 malignant brain cells.

        (Seyfried et al. 2011 Biochim Biophys Acta )

Winter et al.

Other mechanisms?

Anti-inflammation effect?

Other mechanisms?

 A key distinction between “type 1” and “type 2” inflammation is that the latter activates
  bone-marrow derived macrophage in the CNS and/or brain resident microglia.
 Microglia are probably recruited to the glioma microenvironment at all stages of
  malignancy.
 A majority of the macrophages accumulate only after insult or BBB breakdown, when
  chronic “type 2” inflammation is dominant in the glioma microenvironment.

Various processes in which nutrient intake could modulate directly
or indirectly the immune system and/or the growth of cancer.

Hypothesis ( anti-cancer)
1.Warburg effect
2.Oxidative stress
3.Anti-inflammation effects
4.Immune system modulation

            Ketogenic Diet

Glioblastoma Multiforme

Role of ketogenic diet ?

• Glioblastoma multiforme accounts for 12% to 15% of all
  intracranial neoplasms and affects 2 to 3 adults per every 100,000
  in the United States annually.
• In children, glioblastoma multiforme accounts for approximately
  7% to 9% of central nervous system tumors.
• The mean survival rate in adults after diagnosis ranges from 12 to
  18 months with standard therapy and 3 to 6 months without
  therapy.

• There have been few advances in the treatment of glioblastoma
  multiforme in the past 40 years beyond surgery, radiotherapy,
  chemotherapy, and corticosteroids.

The restrictive calorie ketogenic diet has
2 main targets:

1.The primary target is to reduce the glucose
  energy source for cancer
2.The secondary target is the activation of
  genes by calorie restriction that are
  neuroprotective and can induce cancer cell
  apoptosis.

• Current anticancer therapies increase glucose and glutamate levels

First to attempt
• In 1995, Nebeling et al. were the first to attempt
  using the ketogenic diet as a therapy for malignant
  brain cancer in humans.
• The patients were 2 female children with non-
  resectable advanced stage brain tumors that were
  refractory to radiation and chemotherapy.
• In this case report the ketogenic diet was effective in
  managing tumor growth and enhancing progression
  free survival.
                     Nebeling LC, et al. J Am Coll Nutr. 1995;14:202-208.

Metabolic management of glioblastoma multiforme using
standard therapy together with a restricted calorie ketogenic
diet: case report
• In 2010, researchers in Italy published a case report on a single
  65-year-old female patient with glioblastoma multiforme that
  was placed on the restrictive calorie ketogenic diet.
• She was restricted to 600 kcal/day and her glucocorticoids were
  stopped.
• The patient had already received standard radiation treatment
  and chemotherapy.
• While on the diet the patient showed a significant reduction in
  blood glucose with an elevation of urine ketones.
• She experienced a 20% weight reduction while on the diet, but
  most importantly, no new tumor progression was seen during the
  duration of the diet. The patient was not found to have a
  recurrence of glioblastoma multiforme for approximately 8
  months after the diet was stopped and chemotherapy was
  initiated.
                              Zuccoli G, et al. Nutr Metab. 2010;7:33.

• Maintaining a restrictive caloric intake between
  600 to 1200 kcal/day to maintain blood glucose
  range of 50 to 65 mg/dl has been severely
  difficult and often disabling.

• Researchers have noted poor compliance due
  to constant hunger that lead to unauthorized
  food consumption.

Effects of a ketogenic diet on the quality
of life in 16 patients with advanced cancer:
a pilot trial
• In 2011, German researchers evaluated the
  restrictive calorie ketogenic diet in 16 subjects
  with end-stage malignant tumors who had
  exhausted all standard therapies.
• Of the 16 subjects, 5 were able to complete the
  3-month treatment period, and of these 5 none
  experienced further tumor progression while on
  the diet.
                            Schmidt M, et al. Nutr Metab. 2011;8:54.

Schwartz et al. Cancer & Metabolism (2015) 3:3

Animal Model

• In 2002, Seyfried et al. discovered that calorie
  restriction alone was an effective anti-
  angiogenic therapy for recurrent brain tumors
  in a mice model.
                     Mukherjee P, et al. Br J Cancer. 2002;86:1615-1621.
• In 2008, their research showed the restrictive
  calorie ketogenic diet along with
  2-deoxyglucose was more effective than a
  restricted calorie diet alone at inhibiting the
  growth of astrocytomas in mice models.
                                   Marsh J, et al. Nutr Metab. 2008;5:33.

Animal model

Kaplan-Meier analyses of the survival data (Figure 1A) demonstrated a
statistically significant (p

Conclusion:
• KC significantly enhances the anti-tumor effect
  of radiation.
• This suggests that cellular metabolic alterations
  induced through KC may be useful as an
  adjuvant to the current standard of care for the
  treatment of human malignant gliomas.

Ketogenic diet may be useful as an adjuvant to the
current standard of care for the treatment of human
malignant gliomas.

 A prospective, non-blinded, randomised, pilot study will be undertaken in 12
  patients with newly diagnosed glioblastoma treated by surgical resection.
 Patients will be randomised in a ratio of 1:1, using a permuted block randomisation
  method to one of two diets; the modified ketogenic diet and the medium chain
  triglyceride ketogenic diet.
 Primary data collection will take place 12 weeks after starting the diet and
  secondary data collection after 12 months.

Trial Outcome Measures

Case 1

15y10m, female
(2012/01/05) short stature, no menstruation
             Brain MRI: brainstem tumor
(2012/02) patho: Pilocytic Astrocytoma (WHO grade I)
(2012/04) seizures
(2015/08) Ketogenic diet

2012/03/20            2015/08/19

                 KD

                                   51*21 mm
             2018/03/28

                                   32*14 mm

Asian Recipes

More than you can imagine

Case 2
10y, female
(2004/11) syncope
          Brain MRI: brainstem tumor
(2004/11) patho: Desmoplastic Infantile Ganglioglioma
(2004/12) Radiotherapy: 5600 cGy for tumor bed
(2008/8) tumor recurrence with CSF seeding
(2013/08) Radiotherapy: 5600 cGy
(2017/09) Ketogenic diet

2017/06/02

2004/10

               25.9*8.4 mm

                 KD

          2018/05/28

                23.2*6.6 mm

Asian Recipes

43

Rice dumpling (粽子)

Many Asian recipes on the internet

                     Mooncake (月餅)

Feasibility

Measurement,                                      Predict individual
Compliance                                        treatment

Imaging, side effects,
    clinical, QoL
                                                  Dietary regimen,
                                                  Add-on?
                         Enhancing Rx/Cx,
                         Combination

Potential role of IV KD
for cancer treatment ?!

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Acknowlegment:
KETO Group of Chang Gung Children’s Hospital, Taiwan