A high-fat and low-carbohydrate diet was administered as a complementary and alternative therapy to a 54-year-old man suffering from non-small-cell lung cancer (NSCLC) with brain metastasis. Three months after the cessation of chemotherapy and radiotherapy, a ketogenic diet (KD) was initiated. This approach was an attempt to stabilize the disease progression after chemotherapy and radiotherapy. Computed tomography following radiation and chemotherapy showed a reduction in the right frontal lobe lesion from 5.5 cm × 6.2 cm to 4 cm × 2.7 cm, while the mass in the upper-right lung lobe reduced from 6.0 cm × 3.0 cm to 2.0 × 1.8 cm. Two years after KD initiation and without any other therapeutic intervention, the right frontal lobe lesion calcified and decreased in size to 1.9 cm × 1.0 cm, while the size of the lung mass further decreased to 1.7 cm × 1.0 cm. The size of the brain and lung lesion remained stable after nine years of KD therapy. However, dyslipidemia developed after this time which led to the discontinuation of the diet. No tumor relapse or health issues occurred for two years after the discontinuation of the diet. This case report indicates that the inclusion of ketogenic metabolic therapy following radiation and chemotherapy is associated with better clinical and survival outcomes for our patient with metastatic NSCLC.
Despite progress in chemotherapy, radiation, and surgical procedures, malignant cancer continues to be a leading cause of death globally. Therefore, there is a need to develop new therapeutic procedures that are more effective than current approaches. Some factors in the pathophysiology of the malignant cells can possibly suggest improved therapeutic options.
Malignant cancer cells express particular metabolic characteristics that distinguish them from healthy cells. Specifically, most cancer cells lack metabolic versatility due to mitochondrial abnormalities and are largely dependent on glucose for energy according to the Warburg theory of cancer [1,2]. This common phenotype of tumor cells contrasts with that of normal brain cells, which derive energy from ketone bodies when glucose becomes limited . Consequently, it makes sense to question the fate of cancer cells when their primary glycolytic fuel is reduced.
A simple approach is to inhibit glycolysis while increasing circulating ketone bodies. The high-fat/low-carbohydrate ketogenic diet (KD) is a good option for patients with brain cancer. The KD might also limit the availability of glutamine . Glucose and glutamine together provide the majority of energy needed for the growth of tumor cells .
Ketogenic metabolic therapy (KMT) is becoming recognized as an effective complementary or alternative therapeutic strategy for managing cancer [5-7]. Nebeling et al. found that a KD consisting of medium-chain triglycerides provided long-term management of pediatric astrocytomas while enhancing the nutritional status of patients . The findings in human pediatric astrocytoma were confirmed in an experimental mouse model of astrocytoma using a lard-based rodent KD .
Seyfried et al. also demonstrated that dietary energy restriction and restricted KDs that lower blood glucose while elevating blood ketone bodies have anti-tumor and anti-angiogenic effects in several experimental mouse models of brain tumors . Further support for this metabolic cancer therapy has been obtained for human glioblastoma [11-13]. In this study, we describe the favorable course of a patient diagnosed with non-small-cell lung cancer (NSCLC) with neuroendocrine features and brain metastasis who was administered a KD for three months following the completion of radiation and chemotherapy.
A 54-year-old right-handed man presented with headache, dizziness, gait ataxia, vomiting, and blurred vision one week before admission on December 30, 2007. A computed tomography (CT) scan of the brain obtained in the emergency room revealed multiple metastatic lesions in the left cerebellum, right temporal lobe, and frontal lobes bilaterally (Figure 1). The patient’s medical history was unremarkable, but he had smoked heavily (four to five packs/day) for 36 years. Imaging analysis was performed to reveal the primary lesion. A chest CT scan revealed a mass of 6.0 cm × 3.0 cm in the upper-right lobe (Figure 2), and the lung biopsy was compatible with NSCLC with neuroendocrine features (Figure 3). The staging images did not show any other lymph node or metastatic disease.
The patient received whole brain radiation therapy (3,000 Gy over 10 daily sessions) from January 24, 2008, until February 7, 2008. No radiation therapy was performed on the lungs. Paclitaxel/carboplatin chemotherapy was provided from March 3, 2008, until June 17, 2008. The patient received six cycles of chemotherapy with paclitaxel (175 mg/m2) and six cycles of carboplatin AUC every 21 days and showed good tolerance. A KD was initiated in June 2008 during the follow-up phase after chemotherapy and radiation were completed. At this point, chemotherapy and radiation had no effect on reducing primary and secondary tumor lesions.
The KD was administered as a complementary alternative therapy in an attempt to stabilize disease progression. The diet was started with a 1:1 ketogenic ratio and gradually reached 3:1. The diet was adapted to Mediterranean diet patterns due to the patient’s aggravated condition from the disease and chemotherapy to avoid additional side effects. This diet pattern is milder than the classic North American-Northwestern European KD. An example of the diet applied in its final form (3:1) is shown in Table 1.
Figures 4-9 show the first brain CT scan after completion of radiation and chemotherapy, as well as the development until the last follow-up brain CT scan, chest CT scan, and brain magnetic resonance imaging (MRI) scan 10.5 years after the KD initiation. No serious adverse effects were noticed during the course of the KD therapy. The patient developed kidney stones in June 2011, which were easily removed through lithotripsy.
During the course of the KD therapy, glucose levels remained at 60 to 70 mg/dL (3.3-3.9 mmol/L), while the ketone levels were elevated to about 2 mmol/L. These glucose and ketone values produced a glucose-ketone index (GKI) of approximately 1.8, indicating a high therapeutic level of ketosis. The patient’s body weight remained relatively stable during the 10-year KD treatment period (his initial weight was 87 kg, and his final weight was 82 kg). Moreover, during the same period, the patient’s lipidemic profile was stable without the appearance of any dyslipidemia. Table 2 provides a summary of the tumor progression, type of KD, and daily caloric intake in relation to ketone, glucose, lipid, and weight. The KD was terminated 10 years after diet initiation (2018) as the patient developed dyslipidemia (cholesterol >280 mg/dL, triglycerides >300 mg/dL). It has now been almost four years since the patient stopped the KD, and he remains healthy with no evidence of tumor recurrence.
Previous case reports have shown that the KD can be effective in managing primary brain cancer in children and adults [8-12]. However, to our knowledge, no prior case studies have described a therapeutic effect of a KD against metastatic or secondary brain cancer. We attempted to address the cause of the favorable disease course in our patient. The favorable response to therapy in this patient could have been an effect of conventional therapy, the KD therapy, or a combination of these effects.
NSCLC is a highly aggressive pulmonary neuroendocrine tumor, and affected patients generally have a significantly worse prognosis than patients with large-cell carcinomas, even in stage 1 disease [14,15]. Moreover, little has been established regarding a standard treatment strategy for this type of advanced clinical cancer. Growth management is not generally observed after chemo and radiation therapy [16,17]. Remarkably, the patient’s tumor growth, including brain metastasis, was stabilized and even diminished about one year after completion of the standard treatment and long after. The only therapeutic intervention during this period was the KD. Therefore, it is possible that the diet was partly responsible for the patient’s improvement.
The above beneficial effect of the KD is also supported by the fact that no effect on the disease course was observed throughout the latest period when the patient was receiving conventional therapy. It is important to mention that the low-normal glucose levels could have also contributed in part to the restricted tumor growth in our patient. Previous studies in mice and humans with brain cancer have shown that low blood glucose levels are associated with reduced brain tumor growth rate and better survival, while elevated glucose or hyperglycemia contributes to rapid tumor growth and poor patient survival [9,18]. Elevated blood glucose is also a risk factor for breast cancer and NSCLC . It is likely that the combination of both reduced glucose levels and elevated ketone levels contributed to tumor management, as described previously [8,19].
Another interesting point is the lipidemic profile of the patient. The patient developed dyslipidemia only after 10 years on the 3:1 KD without evidence of tumor recurrence. At first glance, this observation could be correlated to the fact that the tumor was no longer active. However, further studies will be needed to determine the origin of dyslipidemia following long-term treatment of cancer patients with KMT.
This case report gives hope that the KD might improve clinical outcomes for some patients with NSCLC. The tumor shrinkage, survival time, spectacular improvement in physical condition, and the restoration of daily attitudes are encouraging for further application of this therapeutic approach to larger numbers of patients.
- Seyfried TN, Mukherjee P: Targeting energy metabolism in brain cancer: review and hypothesis. Nutr Metab (Lond). 2005, 2:30. 10.1186/1743-7075-2-30
- Warburg O: On the origin of cancer cells. Science. 1956, 123:309-14. 10.1126/science.123.3191.309
- Yudkoff M, Daikhin Y, Melø TM, Nissim I, Sonnewald U, Nissim I: The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect. Annu Rev Nutr. 2007, 27:415-30. 10.1146/annurev.nutr.27.061406.093722
- Seyfried TN, Shelton LM: Cancer as a metabolic disease. Nutr Metab (Lond). 2010, 7:7. 10.1186/1743-7075-7-7
- Klement RJ, Bandyopadhyay PS, Champ CE, Walach H: Application of Bayesian evidence synthesis to modelling the effect of ketogenic therapy on survival of high grade glioma patients. Theor Biol Med Model. 2018, 15:12. 10.1186/s12976-018-0084-y
- Weber DD, Aminzadeh-Gohari S, Tulipan J, Catalano L, Feichtinger RG, Kofler B: Ketogenic diet in the treatment of cancer - where do we stand?. Mol Metab. 2020, 33:102-21. 10.1016/j.molmet.2019.06.026
- Seyfried TN, Mukherjee P, Iyikesici MS, Slocum A, Kalamian M, Spinosa JP, Chinopoulos C: Consideration of ketogenic metabolic therapy as a complementary or alternative approach for managing breast cancer. Front Nutr. 2020, 7:21. 10.3389/fnut.2020.00021
- Nebeling LC, Miraldi F, Shurin SB, Lerner E: Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J Am Coll Nutr. 1995, 14:202-8. 10.1080/07315724.1995.10718495
- Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P: Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer. 2003, 89:1375-82. 10.1038/sj.bjc.6601269
- Poff AM, Ari C, Arnold P, Seyfried TN, D'Agostino DP: Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. Int J Cancer. 2014, 135:1711-20. 10.1002/ijc.28809
- Elsakka AM, Bary MA, Abdelzaher E, Elnaggar M, Kalamian M, Mukherjee P, Seyfried TN: Management of glioblastoma multiforme in a patient treated with ketogenic metabolic therapy and modified standard of care: a 24-month follow-up. Front Nutr. 2018, 5:20. 10.3389/fnut.2018.00020
- Vallejo FA, Shah SS, de Cordoba N, et al.: The contribution of ketone bodies to glycolytic inhibition for the treatment of adult and pediatric glioblastoma. J Neurooncol. 2020, 147:317-26. 10.1007/s11060-020-03431-w
- Schwartz K, Chang HT, Nikolai M, et al.: Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer Metab. 2015, 3:3. 10.1186/s40170-015-0129-1
- Kim DY, Lee KW, Yun T, et al.: Efficacy of platinum-based chemotherapy after cranial radiation in patients with brain metastasis from non-small cell lung cancer. Oncol Rep. 2005, 14:207-11. 10.1200/jco.2004.22.90140.1575
- Battafarano RJ, Fernandez FG, Ritter J, Meyers BF, Guthrie TJ, Cooper JD, Patterson GA: Large cell neuroendocrine carcinoma: an aggressive form of non-small cell lung cancer. J Thorac Cardiovasc Surg. 2005, 130:166-72. 10.1016/j.jtcvs.2005.02.064
- Yamazaki S, Sekine I, Matsuno Y, et al.: Clinical responses of large cell neuroendocrine carcinoma of the lung to cisplatin-based chemotherapy. Lung Cancer. 2005, 49:217-23. 10.1016/j.lungcan.2005.01.008
- Rossi G, Cavazza A, Marchioni A, et al.: Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFRalpha, PDGFRbeta, and Met in large-cell neuroendocrine carcinoma of the lung. J Clin Oncol. 2005, 23:8774-85. 10.1200/JCO.2005.02.8233
- Derr RL, Ye X, Islas MU, Desideri S, Saudek CD, Grossman SA: Association between hyperglycemia and survival in patients with newly diagnosed glioblastoma. J Clin Oncol. 2009, 27:1082-6. 10.1200/JCO.2008.19.1098
- Obaid QA, Khudair KK, Al-Shammari AM: Glucose deprivation using 2-deoxyglucose and acarbose induce metabolic oxidative stress and apoptosis in female mice bearing breast cancer. Biochimie. 2022, 195:59-66. 10.1016/j.biochi.2022.01.007
Restricted Ketogenic Diet Therapy for Primary Lung Cancer With Metastasis to the Brain: A Case Report
Ethics Statement and Conflict of Interest Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Cite this article as:
Evangeliou A E, Spilioti M G, Vassilakou D, et al. (August 02, 2022) Restricted Ketogenic Diet Therapy for Primary Lung Cancer With Metastasis to the Brain: A Case Report. Cureus 14(8): e27603. doi:10.7759/cureus.27603
Peer review began: July 08, 2022
Peer review concluded: July 30, 2022
Published: August 02, 2022
© Copyright 2022
Evangeliou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.