Consuming a Ketogenic Diet while Receiving Radiation and Chemotherapy for Locally Advanced Lung Cancer and Pancreatic Cancer: The University of Iowa Experience of Two Phase 1 Clinical Trials
Amir Zahra, Melissa A Fath, Emyleigh Opat, Kranti A Mapuskar, Sudershan K Bhatia, Daniel C Ma, Samuel N Rodman III, Travis P Snyders, Catherine A Chenard, Julie M Eichenberger-Gilmore, Kellie L Bodeker, Logan Ahmann, Brian J Smith, Sandy A Vollstedt, Heather A Brown, Taher Abu Hejleh, Gerald H Clamon, Daniel J Berg, Luke I Szweda, Douglas R Spitz, John M Buatti, Bryan G Allen, Amir Zahra, Melissa A Fath, Emyleigh Opat, Kranti A Mapuskar, Sudershan K Bhatia, Daniel C Ma, Samuel N Rodman III, Travis P Snyders, Catherine A Chenard, Julie M Eichenberger-Gilmore, Kellie L Bodeker, Logan Ahmann, Brian J Smith, Sandy A Vollstedt, Heather A Brown, Taher Abu Hejleh, Gerald H Clamon, Daniel J Berg, Luke I Szweda, Douglas R Spitz, John M Buatti, Bryan G Allen
Abstract
Ketogenic diets are low in carbohydrates and high in fat, which forces cells to rely more heavily upon mitochondrial oxidation of fatty acids for energy. Relative to normal cells, cancer cells are believed to exist under a condition of chronic mitochondrial oxidative stress that is compensated for by increases in glucose metabolism to generate reducing equivalents. In this study we tested the hypothesis that a ketogenic diet concurrent with radiation and chemotherapy would be clinically tolerable in locally advanced non-small cell lung cancer (NSCLC) and pancreatic cancer and could potentially exploit cancer cell oxidative metabolism to improve therapeutic outcomes. Mice bearing MIA PaCa-2 pancreatic cancer xenografts were fed either a ketogenic diet or standard rodent chow, treated with conventionally fractionated radiation (2 Gy/fraction), and tumor growth rates were assessed daily. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modfied proteins as a marker of oxidative stress. Based on this and another previously published preclinical study, phase 1 clinical trials in locally advanced NSCLC and pancreatic cancer were initiated, combining standard radiation and chemotherapy with a ketogenic diet for six weeks (NSCLC) or five weeks (pancreatic cancer). The xenograft experiments demonstrated prolonged survival and increased 4HNE-modfied proteins in animals consuming a ketogenic diet combined with radiation compared to radiation alone. In the phase 1 clinical trial, over a period of three years, seven NSCLC patients enrolled in the study. Of these, four were unable to comply with the diet and withdrew, two completed the study and one was withdrawn due to a dose-limiting toxicity. Over the same time period, two pancreatic cancer patients enrolled in the trial. Of these, one completed the study and the other was withdrawn due to a dose-limiting toxicity. The preclinical experiments demonstrate that a ketogenic diet increases radiation sensitivity in a pancreatic cancer xenograft model. However, patients with locally advanced NSCLC and pancreatic cancer receiving concurrent radiotherapy and chemotherapy had suboptimal compliance to the oral ketogenic diet and thus, poor tolerance.
Figures
![Figure 1. Schematic overview of the ketolung…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5510645/bin/nihms874266f1.jpg)
![Figure 2. Mice fed KDs had lower…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5510645/bin/nihms874266f2.jpg)
Figure 3. Feeding a Ketogenic Diet Sensitizes…
Figure 3. Feeding a Ketogenic Diet Sensitizes Mia PaCa-2 Human Pancreatic Cancer Xenografts to Radiation
Figure 4. KD increases 4HNE-modified proteins in…
Figure 4. KD increases 4HNE-modified proteins in pancreas cancer xenografts
Equivalent protein quantities isolated from…
Figure 5. Circulating levels of ketones in…
Figure 5. Circulating levels of ketones in subjects consuming a 4:1 ketogenic diet while receiving…
Figure 6. Serum glucose levels in subjects…
Figure 6. Serum glucose levels in subjects compliant with the 4:1 ketogenic diet
Figure 7. Lung and pancreas cancer subjects…
Figure 7. Lung and pancreas cancer subjects on a 4:1 ketogenic diet have significantly higher…
- Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts.Allen BG, Bhatia SK, Buatti JM, Brandt KE, Lindholm KE, Button AM, Szweda LI, Smith BJ, Spitz DR, Fath MA. Allen BG, et al. Clin Cancer Res. 2013 Jul 15;19(14):3905-13. doi: 10.1158/1078-0432.CCR-12-0287. Epub 2013 Jun 6. Clin Cancer Res. 2013. PMID: 23743570 Free PMC article.
- Ketogenic Diet with Concurrent Chemoradiation in Head and Neck Squamous Cell Carcinoma: Preclinical and Phase 1 Trial Results.Ma DC, Anderson CM, Rodman SN, Buranasudja V, McCormick ML, Davis A, Loth E, Bodeker KL, Ahmann L, Parkhurst JR, Sun W, Follmer KR, Simons AL, Buatti JM, Spitz DR, Fath MA, Allen BG. Ma DC, et al. Radiat Res. 2021 Aug 1;196(2):213-224. doi: 10.1667/RADE-20-00150.1. Radiat Res. 2021. PMID: 34087943 Free PMC article. Clinical Trial.
- A phase II study of oral S-1 with concurrent radiotherapy followed by chemotherapy with S-1 alone for locally advanced pancreatic cancer.Shinchi H, Maemura K, Mataki Y, Kurahara H, Sakoda M, Ueno S, Hiraki Y, Nakajo M, Natsugoe S, Takao S. Shinchi H, et al. J Hepatobiliary Pancreat Sci. 2012 Mar;19(2):152-8. doi: 10.1007/s00534-011-0400-y. J Hepatobiliary Pancreat Sci. 2012. PMID: 21647560 Clinical Trial.
- Chemoradiotherapy of locally advanced nonsmall cell lung cancer: state of the art and perspectives.Antoni D, Mornex F. Antoni D, et al. Curr Opin Oncol. 2016 Mar;28(2):104-9. doi: 10.1097/CCO.0000000000000265. Curr Opin Oncol. 2016. PMID: 26848885 Review.
- Combined chemotherapy and radiation in locally advanced non-small cell lung cancer.Belani CP, Aisner J. Belani CP, et al. Semin Oncol. 1994 Jun;21(3 Suppl 6):79-90. Semin Oncol. 1994. PMID: 8052878 Review.
- Diet as a Factor Supporting Lung Cancer Treatment-A Systematic Review.Polański J, Świątoniowska-Lonc N, Kołaczyńska S, Chabowski M. Polański J, et al. Nutrients. 2023 Mar 19;15(6):1477. doi: 10.3390/nu15061477. Nutrients. 2023. PMID: 36986207 Free PMC article. Review.
- A bibliometric analysis of Mediterranean diet on cancer from 2012 to 2021.Liu Y, Lu J. Liu Y, et al. Front Nutr. 2023 Feb 8;10:1128432. doi: 10.3389/fnut.2023.1128432. eCollection 2023. Front Nutr. 2023. PMID: 36845049 Free PMC article.
- Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy.Padinharayil H, Rai V, George A. Padinharayil H, et al. Cancers (Basel). 2023 Feb 8;15(4):1070. doi: 10.3390/cancers15041070. Cancers (Basel). 2023. PMID: 36831413 Free PMC article. Review.
- Nutraceuticals as Supportive Therapeutic Agents in Diabetes and Pancreatic Ductal Adenocarcinoma: A Systematic Review.Mikolaskova I, Crnogorac-Jurcevic T, Smolkova B, Hunakova L. Mikolaskova I, et al. Biology (Basel). 2023 Jan 19;12(2):158. doi: 10.3390/biology12020158. Biology (Basel). 2023. PMID: 36829437 Free PMC article. Review.
- The Role of Ketogenic Diet in the Treatment of Neuroblastoma.Makuku R, Sinaei Far Z, Khalili N, Moyo A, Razi S, Keshavarz-Fathi M, Mahmoudi M, Rezaei N. Makuku R, et al. Integr Cancer Ther. 2023 Jan-Dec;22:15347354221150787. doi: 10.1177/15347354221150787. Integr Cancer Ther. 2023. PMID: 36752115 Free PMC article. Review.
- Clinical Trial, Phase I
- Controlled Clinical Trial
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Aged
- Aged, 80 and over
- Animals
- Cell Line, Tumor
- Chemoradiotherapy / methods*
- Diet Therapy / methods*
- Diet, Ketogenic / methods*
- Female
- Humans
- Iowa
- Lung Neoplasms / diagnosis*
- Lung Neoplasms / therapy*
- Male
- Mice
- Mice, Nude
- Middle Aged
- Pancreatic Neoplasms / diagnosis
- Pancreatic Neoplasms / therapy*
- Treatment Outcome
- Full Text Sources
- Other Literature Sources
- Medical
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![Figure 3. Feeding a Ketogenic Diet Sensitizes…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5510645/bin/nihms874266f3.jpg)
Figure 4. KD increases 4HNE-modified proteins in…
Figure 4. KD increases 4HNE-modified proteins in pancreas cancer xenografts
Equivalent protein quantities isolated from…
Figure 5. Circulating levels of ketones in…
Figure 5. Circulating levels of ketones in subjects consuming a 4:1 ketogenic diet while receiving…
Figure 6. Serum glucose levels in subjects…
Figure 6. Serum glucose levels in subjects compliant with the 4:1 ketogenic diet
Figure 7. Lung and pancreas cancer subjects…
Figure 7. Lung and pancreas cancer subjects on a 4:1 ketogenic diet have significantly higher…
- Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts.Allen BG, Bhatia SK, Buatti JM, Brandt KE, Lindholm KE, Button AM, Szweda LI, Smith BJ, Spitz DR, Fath MA. Allen BG, et al. Clin Cancer Res. 2013 Jul 15;19(14):3905-13. doi: 10.1158/1078-0432.CCR-12-0287. Epub 2013 Jun 6. Clin Cancer Res. 2013. PMID: 23743570 Free PMC article.
- Ketogenic Diet with Concurrent Chemoradiation in Head and Neck Squamous Cell Carcinoma: Preclinical and Phase 1 Trial Results.Ma DC, Anderson CM, Rodman SN, Buranasudja V, McCormick ML, Davis A, Loth E, Bodeker KL, Ahmann L, Parkhurst JR, Sun W, Follmer KR, Simons AL, Buatti JM, Spitz DR, Fath MA, Allen BG. Ma DC, et al. Radiat Res. 2021 Aug 1;196(2):213-224. doi: 10.1667/RADE-20-00150.1. Radiat Res. 2021. PMID: 34087943 Free PMC article. Clinical Trial.
- A phase II study of oral S-1 with concurrent radiotherapy followed by chemotherapy with S-1 alone for locally advanced pancreatic cancer.Shinchi H, Maemura K, Mataki Y, Kurahara H, Sakoda M, Ueno S, Hiraki Y, Nakajo M, Natsugoe S, Takao S. Shinchi H, et al. J Hepatobiliary Pancreat Sci. 2012 Mar;19(2):152-8. doi: 10.1007/s00534-011-0400-y. J Hepatobiliary Pancreat Sci. 2012. PMID: 21647560 Clinical Trial.
- Chemoradiotherapy of locally advanced nonsmall cell lung cancer: state of the art and perspectives.Antoni D, Mornex F. Antoni D, et al. Curr Opin Oncol. 2016 Mar;28(2):104-9. doi: 10.1097/CCO.0000000000000265. Curr Opin Oncol. 2016. PMID: 26848885 Review.
- Combined chemotherapy and radiation in locally advanced non-small cell lung cancer.Belani CP, Aisner J. Belani CP, et al. Semin Oncol. 1994 Jun;21(3 Suppl 6):79-90. Semin Oncol. 1994. PMID: 8052878 Review.
- Diet as a Factor Supporting Lung Cancer Treatment-A Systematic Review.Polański J, Świątoniowska-Lonc N, Kołaczyńska S, Chabowski M. Polański J, et al. Nutrients. 2023 Mar 19;15(6):1477. doi: 10.3390/nu15061477. Nutrients. 2023. PMID: 36986207 Free PMC article. Review.
- A bibliometric analysis of Mediterranean diet on cancer from 2012 to 2021.Liu Y, Lu J. Liu Y, et al. Front Nutr. 2023 Feb 8;10:1128432. doi: 10.3389/fnut.2023.1128432. eCollection 2023. Front Nutr. 2023. PMID: 36845049 Free PMC article.
- Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy.Padinharayil H, Rai V, George A. Padinharayil H, et al. Cancers (Basel). 2023 Feb 8;15(4):1070. doi: 10.3390/cancers15041070. Cancers (Basel). 2023. PMID: 36831413 Free PMC article. Review.
- Nutraceuticals as Supportive Therapeutic Agents in Diabetes and Pancreatic Ductal Adenocarcinoma: A Systematic Review.Mikolaskova I, Crnogorac-Jurcevic T, Smolkova B, Hunakova L. Mikolaskova I, et al. Biology (Basel). 2023 Jan 19;12(2):158. doi: 10.3390/biology12020158. Biology (Basel). 2023. PMID: 36829437 Free PMC article. Review.
- The Role of Ketogenic Diet in the Treatment of Neuroblastoma.Makuku R, Sinaei Far Z, Khalili N, Moyo A, Razi S, Keshavarz-Fathi M, Mahmoudi M, Rezaei N. Makuku R, et al. Integr Cancer Ther. 2023 Jan-Dec;22:15347354221150787. doi: 10.1177/15347354221150787. Integr Cancer Ther. 2023. PMID: 36752115 Free PMC article. Review.
- Clinical Trial, Phase I
- Controlled Clinical Trial
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Aged
- Aged, 80 and over
- Animals
- Cell Line, Tumor
- Chemoradiotherapy / methods*
- Diet Therapy / methods*
- Diet, Ketogenic / methods*
- Female
- Humans
- Iowa
- Lung Neoplasms / diagnosis*
- Lung Neoplasms / therapy*
- Male
- Mice
- Mice, Nude
- Middle Aged
- Pancreatic Neoplasms / diagnosis
- Pancreatic Neoplasms / therapy*
- Treatment Outcome
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 4. KD increases 4HNE-modified proteins in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5510645/bin/nihms874266f4.jpg)
Figure 5. Circulating levels of ketones in…
Figure 5. Circulating levels of ketones in subjects consuming a 4:1 ketogenic diet while receiving…
Figure 6. Serum glucose levels in subjects…
Figure 6. Serum glucose levels in subjects compliant with the 4:1 ketogenic diet
Figure 7. Lung and pancreas cancer subjects…
Figure 7. Lung and pancreas cancer subjects on a 4:1 ketogenic diet have significantly higher…
![Figure 5. Circulating levels of ketones in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5510645/bin/nihms874266f5.jpg)
![Figure 6. Serum glucose levels in subjects…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5510645/bin/nihms874266f6.jpg)
![Figure 7. Lung and pancreas cancer subjects…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5510645/bin/nihms874266f7.jpg)
Source: PubMed