Reducing Insulin, Growth Hormones, and Tumors
| Status: | Recruiting |
|---|---|
| Conditions: | Lung Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 4/5/2019 |
| Start Date: | December 21, 2018 |
| End Date: | June 2021 |
| Contact: | Jessica Kuzma, PhD |
| Email: | jkuzma@fredhutch.org |
| Phone: | 206.667.4168 |
The Impact of Diet Quality on Biomarkers Associated With Lung Cancer Outcomes: Reducing Insulin, Growth Hormones, and Tumors (RIGHT Study)
The objective of this project is to compare the effect of two widely implemented cancer
diets, differing drastically in macronutrient content, on biomarkers of inflammation,
compared to a control diet.
Diet A will be a low-carbohydrate, high-fat ketogenic-type diet with an emphasis on whole
foods. By limiting carbohydrate, the diet will have an extremely low glycemic load, thereby
minimizing diurnal glucose and insulin excursions.
Diet B will be a low-fat, high-carbohydrate whole foods plant-based diet. It will include
only fiber-rich, low-glycemic index sources of carbohydrates and largely eliminate animal
protein, which will minimize rapid spikes in blood glucose and insulin and the production of
IGF-1. This diet is also hypothesized to improve glucose tolerance and insulin sensitivity,
which should further help minimize diurnal glycemic and insulinemic excursions.
Both diets will be compared to a control diet based on the 2015 USDA Dietary Guidelines for
Americans (Diet C) in patients suffering from advanced lung cancer as they are completing
medical therapy.
The overarching hypothesis motivating this work is that a nutrient dense diet that minimizes
known factors involved in tumor growth and progression may improve the effectiveness of
therapy. Our specific hypothesis is that participants following either of the experimental
diets, A or B, will experience a reduction in biomarkers of insulin resistance and chronic
inflammation, both of which are known risk factors for progression in lung cancer, and a
greater median time to progression compared to those on the control diet (Diet C).
diets, differing drastically in macronutrient content, on biomarkers of inflammation,
compared to a control diet.
Diet A will be a low-carbohydrate, high-fat ketogenic-type diet with an emphasis on whole
foods. By limiting carbohydrate, the diet will have an extremely low glycemic load, thereby
minimizing diurnal glucose and insulin excursions.
Diet B will be a low-fat, high-carbohydrate whole foods plant-based diet. It will include
only fiber-rich, low-glycemic index sources of carbohydrates and largely eliminate animal
protein, which will minimize rapid spikes in blood glucose and insulin and the production of
IGF-1. This diet is also hypothesized to improve glucose tolerance and insulin sensitivity,
which should further help minimize diurnal glycemic and insulinemic excursions.
Both diets will be compared to a control diet based on the 2015 USDA Dietary Guidelines for
Americans (Diet C) in patients suffering from advanced lung cancer as they are completing
medical therapy.
The overarching hypothesis motivating this work is that a nutrient dense diet that minimizes
known factors involved in tumor growth and progression may improve the effectiveness of
therapy. Our specific hypothesis is that participants following either of the experimental
diets, A or B, will experience a reduction in biomarkers of insulin resistance and chronic
inflammation, both of which are known risk factors for progression in lung cancer, and a
greater median time to progression compared to those on the control diet (Diet C).
Little is known about the role of diet in the treatment of lung and other cancers, yet
physicians are constantly confronted with the question 'what should I eat' by their patients.
Very few randomized controlled dietary interventions have been carried out in this
population, hence physicians and dietitians must use their best professional judgement to
provide nutrition advice to their patients. Because most believe that nutrition is an
important part of the treatment process, patients are eager to implement dietary
recommendations and take control of this portion of their medical care. As such, upwards of
64% of patients use the internet to access health information related to cancer treatment
with nutrition websites being among the most popular sites visited. However, the dietary
advice on the internet aimed at cancer patients is highly discrepant, and even so among
cancer treatment centers and research institutions. Within the National Comprehensive Cancer
Network (NCCN), of which Fred Hutchinson is a member, only 43% (9 of 21 centers) either
provide nutritional information on their website or linked to outside websites. Of those,
roughly half recommended a low-fat diet during cancer treatment and the other half
recommended a calorie-dense eating plan with the inclusion of high-fat foods. Clearly, this
presents a potential pitfall for patients as they, without guidance from their physician or
dietitian, may follow dietary advice that is misleading or potentially harmful.
While there is a need for further studies to elucidate the role diet plays during the
treatment of cancers in general, lung cancer in particular is understudied in comparison to
other types of cancers, and presents a unique opportunity to study the impact of diet during
treatment. Primarily, lung cancer patients do not typically suffer from constraints to eating
that affect colorectal, esophageal, or head/throat/neck cancer sufferers. Therefore, diet
interventions using whole-foods may be fairly well tolerated in this population. A review of
nutrition interventions in lung cancer patients carried out through October 2012 indicated
that only three controlled studies in 149 patients had been completed, all of which used
nutritional supplement products to prevent unintentional weight loss. The authors concluded
that nutrition interventions in this population are safe and that more research is needed to
determine optimal nutrition recommendations for advanced, inoperable lung cancers
. Through the manipulation of diet, it is possible to selectively target key pathways
involved in cancer growth and proliferation. For instance, it is known that cancer cells
generate energy through the process of anaerobic glycolysis (the Warburg Effect) which relies
primarily on glucose as a fuel source. Evidence from in vitro studies of non-small cell lung
cancer (NSCLC) suggests that reducing the glucose availability from the diet might be
particularly effective in the treatment of squamous cell carcinomas because the glucose
transporter (GLUT-1) expression is markedly elevated in these cancer cells and is associated
with enhanced uptake of, and dependence upon, glucose. Case-control studies show that dietary
glycemic index is strongly associated with squamous cell carcinoma among NSCLC patients,
suggesting that dietary strategies that limit carbohydrate may be effective in 'starving'
these predominately glycolytic cells. A diet pattern in which overall energy is not limited,
but sources of glucose are selectively reduced, is one mechanism by which cancer progression
might be abated. Such low-carbohydrate or - in their most extreme form - ketogenic diets,
which provide energy primarily from fat and protein while minimizing carbohydrates, are
increasingly shown to be therapeutic for the treatment of glioblastoma and other cancers, as
well as neurological diseases, including epilepsy, and cardiovascular disease risk factors.
It is also known that activation of the IGF pathway is critical for tumor cell proliferation,
invasiveness, and survival in NSCLC and downregulation of this pathway through dietary
manipulation might also be an effective means to suppress cancer growth. The insulin-like
growth factor-1 receptor (IGF-1R) is abundantly present on surfaces of tumor cells, and high
circulating levels of IGF-1, the ligand for the IGF-1R, are a risk factor for future lung
malignancy. As individuals who consume diets high in protein from animal sources have greater
levels of circulating IGF-1 compared to those consuming a vegetarian/vegan diet, limiting the
intake of animal products may be an intriguing dietary strategy that might influence cancer
progression. In our lab, we have shown that insulin sensitivity and glucose tolerance
improved after subjects adhered to a diet rich in whole grains, legumes, fruits, and
vegetables, that excluded refined sources of energy (added sugar, refined grains, added fats
and oils) (Kratz et al. unpublished data). This suggests that such a diet would also reduce
the diurnal exposure of tumor cells to both glucose and insulin, which would decrease the
availability of fuel and growth hormones for cancer cells. Taken together, both
low-carbohydrate/ketogenic diets and low-fat, whole foods plant-based diets could plausibly
affect pathways involved in cancer growth or progression by minimizing diurnal exposure to
glucose, insulin, and IGF-1.
physicians are constantly confronted with the question 'what should I eat' by their patients.
Very few randomized controlled dietary interventions have been carried out in this
population, hence physicians and dietitians must use their best professional judgement to
provide nutrition advice to their patients. Because most believe that nutrition is an
important part of the treatment process, patients are eager to implement dietary
recommendations and take control of this portion of their medical care. As such, upwards of
64% of patients use the internet to access health information related to cancer treatment
with nutrition websites being among the most popular sites visited. However, the dietary
advice on the internet aimed at cancer patients is highly discrepant, and even so among
cancer treatment centers and research institutions. Within the National Comprehensive Cancer
Network (NCCN), of which Fred Hutchinson is a member, only 43% (9 of 21 centers) either
provide nutritional information on their website or linked to outside websites. Of those,
roughly half recommended a low-fat diet during cancer treatment and the other half
recommended a calorie-dense eating plan with the inclusion of high-fat foods. Clearly, this
presents a potential pitfall for patients as they, without guidance from their physician or
dietitian, may follow dietary advice that is misleading or potentially harmful.
While there is a need for further studies to elucidate the role diet plays during the
treatment of cancers in general, lung cancer in particular is understudied in comparison to
other types of cancers, and presents a unique opportunity to study the impact of diet during
treatment. Primarily, lung cancer patients do not typically suffer from constraints to eating
that affect colorectal, esophageal, or head/throat/neck cancer sufferers. Therefore, diet
interventions using whole-foods may be fairly well tolerated in this population. A review of
nutrition interventions in lung cancer patients carried out through October 2012 indicated
that only three controlled studies in 149 patients had been completed, all of which used
nutritional supplement products to prevent unintentional weight loss. The authors concluded
that nutrition interventions in this population are safe and that more research is needed to
determine optimal nutrition recommendations for advanced, inoperable lung cancers
. Through the manipulation of diet, it is possible to selectively target key pathways
involved in cancer growth and proliferation. For instance, it is known that cancer cells
generate energy through the process of anaerobic glycolysis (the Warburg Effect) which relies
primarily on glucose as a fuel source. Evidence from in vitro studies of non-small cell lung
cancer (NSCLC) suggests that reducing the glucose availability from the diet might be
particularly effective in the treatment of squamous cell carcinomas because the glucose
transporter (GLUT-1) expression is markedly elevated in these cancer cells and is associated
with enhanced uptake of, and dependence upon, glucose. Case-control studies show that dietary
glycemic index is strongly associated with squamous cell carcinoma among NSCLC patients,
suggesting that dietary strategies that limit carbohydrate may be effective in 'starving'
these predominately glycolytic cells. A diet pattern in which overall energy is not limited,
but sources of glucose are selectively reduced, is one mechanism by which cancer progression
might be abated. Such low-carbohydrate or - in their most extreme form - ketogenic diets,
which provide energy primarily from fat and protein while minimizing carbohydrates, are
increasingly shown to be therapeutic for the treatment of glioblastoma and other cancers, as
well as neurological diseases, including epilepsy, and cardiovascular disease risk factors.
It is also known that activation of the IGF pathway is critical for tumor cell proliferation,
invasiveness, and survival in NSCLC and downregulation of this pathway through dietary
manipulation might also be an effective means to suppress cancer growth. The insulin-like
growth factor-1 receptor (IGF-1R) is abundantly present on surfaces of tumor cells, and high
circulating levels of IGF-1, the ligand for the IGF-1R, are a risk factor for future lung
malignancy. As individuals who consume diets high in protein from animal sources have greater
levels of circulating IGF-1 compared to those consuming a vegetarian/vegan diet, limiting the
intake of animal products may be an intriguing dietary strategy that might influence cancer
progression. In our lab, we have shown that insulin sensitivity and glucose tolerance
improved after subjects adhered to a diet rich in whole grains, legumes, fruits, and
vegetables, that excluded refined sources of energy (added sugar, refined grains, added fats
and oils) (Kratz et al. unpublished data). This suggests that such a diet would also reduce
the diurnal exposure of tumor cells to both glucose and insulin, which would decrease the
availability of fuel and growth hormones for cancer cells. Taken together, both
low-carbohydrate/ketogenic diets and low-fat, whole foods plant-based diets could plausibly
affect pathways involved in cancer growth or progression by minimizing diurnal exposure to
glucose, insulin, and IGF-1.
Inclusion Criteria:
- Stage IIIB and IV non-small cell adenocarcinoma or squamous cell carcinoma, and
receiving treatment at the Seattle Cancer Care Alliance (SCCA)
- Body mass index (BMI) >= 20 kg/m^2
- Body weight within 10% of current weight within the 3 months before starting the study
- Able and willing to attend bi-weekly dietary support sessions at the Seattle Cancer
Care Alliance (SCCA) during the initial 12-week intervention period
- Willing and able to follow the dietary regimen
- Willing to maintain usual lifestyle habits (other than diet) throughout the study
(e.g., physical activity habits)
- Ability to understand, speak, and write in English
- Ability to provide informed written consent
Exclusion Criteria:
- Neuroendocrine large cell carcinoma or atypical carcinoids with metastatic disease
- Use of antidiabetic medications or insulin within the last 6 months
- Presence of grade 2 weight loss, cachexia, and/or severe nausea
- Current participation in therapeutic first line trial
- Alcohol intake > 2 drinks per day
- Major dietary restriction, as determined by the researcher
- Other significant health condition as determined by the researcher
We found this trial at
1
site
Seattle, Washington 98109
Principal Investigator: Mario Kratz, PhD
Phone: 206-667-4168
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