“The cases that keep me restless at night - too much of a good thing may be a bad thing, strive for the Economy of Balance."
Robert was a loving husband, father, and remarkable engineer who recently died of metastatic pancreatic cancer after a tough 14-month battle. Pancreatic cancer is increasing in incidence and now is the third leading cause of cancer death with a median survival of typically nine months. Robert presented with the typical digestive symptoms, and workup showed early regional spread prompting upfront chemotherapy and SBRT (focal high dose radiation) to enable surgical resection. He responded initially, but in the period, leading to surgery, new metastasis were found in his liver. He then underwent second-course chemotherapy and combined it with an off label veterinary anti-parasite medication. He had good response based on his tumor marker CA 19 –9. Unfortunately, this response was temporary, and he proceeded to a local university in southern Florida to access a newly released lipophilic irinotecan during formulation for pancreatic cancer.
I met Robert at this point in his care as he was a childhood friend of one of my bulletproof coaching colleagues. Robert was interested in the metabolic protocol that Care Oncology offers to patients along with their local standard of care therapies. Robert was truly amazing in his regimented engineering approach and escalating understanding of the metabolic oncology literature. He started the new chemotherapy and metabolic protocol, and although things were stable for a few months, the chemotherapy was harh for him to tolerate. The tumor marker stayed about the same and did not dramatically regress or progress. He then looked at other protocols but dramatically stepped up the "full court press" using fasting, additional supplements, and CBD/cannabis. In addition, the new strategy included adding high-dose vitamin C and hyperbaric oxygen twice weekly. His superhuman efforts were costly in time and money, and unfortunately his tumor marker continued to gallop almost as if all these efforts accelerated his tumor growth. Most pancreatic cancers are K-ras mutated and thus metabolically more flexible. Ultimately, Robert became severely cachectic and had to stop everything and passed away with hospice two weeks later.
Robert and I were in constant communication as I raised concerns that maybe he was pushing his body too hard and exceeding it's tolerance and recovery capacity. His course would not raise eyebrows with oncologists observing the usual pancreatic cancer pattern; however, I continued to seek out questions and concerns of what we could've done differently. Do too many hermetic impacts like what Robert used above potentially overrun the body's recovery systems in the background of metastatic cancer? Can a metastatic multiply recurrent cancer usurp autophagy function and thus fasting and other stressors favor the tumor biology over the normal tissue health? I've since had another patient with metastatic colorectal cancer looking like he is going down the same path, having pushed too hard and now has galloping cancer progression. Hopefully, this literature inquiry will help us better understand this complex interplay between our body's immune function and cancer cell control.
Considerable controversy surrounds the use of fasting and caloric restriction in patients with cancer. Although several lines of evidence suggest that these dietary modifications confer better outcomes, other conflicting reports note that these strategies can exacerbate issues in patients.(1) According to one estimate, malnutrition and sarcopenia manifests in upwards of 80% of cancer patients.(2) Consequently, oncologists must weigh the metabolic modulatory benefits of fasting against the risk of continued weight loss and resulting side effects. This brief review endeavors to explore the scientific merits of these dietary strategies, along with possible drawbacks and contraindications in the clinical setting.
Accumulating preclinical evidence suggests that short-term fasting enhances the efficacy and tolerability of chemotherapy.(3) When confronting nutrient deprivation, healthy cells divert energy away from growth processes and reallocate it towards maintenance and repair pathways. Cancer cells, in contrast, lack such adaptability and struggle to thrive in nutrient-deficient, cytotoxic environments.(4) At a metabolic level, cancer cells also chiefly depend on glycolysis to sustain abnormally high rates of cellular proliferation. By cutting glucose availability, fasting forces tumorous cells to shift towards oxidative phosphorylation. This energetic switch, dubbed the “anti-Warburg effect,” induces oxidative stress and apoptosis.(5) Concentrations of growth factors like IGF-1 also fall in response to energy restricted diets and may further explain why caloric restrictions may impede tumor formation. As a nutrient-responsive growth factor, IGF-1 influences the activation of the Ras/MAPK and PI3K/AKT signaling pathways. Initiation of the Ras/MAPK downstream signaling leads to expression of genes promoting cell growth and proliferation, whereas PI3K/AKT activation results in increased glucose metabolism.(6) Investigators have previously demonstrated that addition of exogenous IGF-1 results in a reversal of anticancer effects caused by caloric restriction, further supporting the idea that it is essential for tumorigenesis.(7)
Critically, AMP-activated protein kinase (AMPK) activity rises as glucose levels fall, leading to the stimulation of autophagy and further cell growth inhibition. Autophagy, an intracellular degradation process, occurs under stressful conditions and can help or hinder tumor development.(8) The differential effects of autophagy may stem from the fact that tumor cells have varying levels of active AMPK. Activation of AMPK in tumor cells with previously low levels may lead to enhanced immune surveillance, whereas tumors with highly active AMPK or autophagy may be treatment resistant.(4) Emerging evidence suggests that many anticancer drugs, like those used in the CareOncology protocol, influence the AMPK and autophagy pathways and explain their anti-angiogenic and anti-proliferative effects.(9) In one investigation, researchers observed a correlation between AMPK activation and increased overall survival in non-small cell lung cancer (NSCLC). Additionally, study authors discovered that AMPK expression levels were significantly higher in non-smokers versus current smokers (P = 0.045).(10) Beyond NSCLC, separate studies are revealing associations between falling AMPK expression and poorer prognoses in liver cancer. As AMPK activity decreases, the clinical phenotype observed in practice becomes more aggressive.(11) Other pre-clinical studies show AMPK influencing the development of cancers, including melanoma, breast cancer, prostate cancer, ovarian cancer, and leukemias.(12) Because AMPK modulates cellular metabolism, medications targeting it or metabolism generally may be promising in the treatment and prevention of cancer.(13)
Previous clinical investigations of fasting suggest that side effects are mild, although it is not suitable in patients with certain pre-existing conditions. Patients on fasting regimens and chemotherapy most commonly report headaches, dizziness, nausea, dyspepsia, and fatigue, with toxicities always being grade 2 or below.(4) Historically, weight loss during fasting ranges from 0.3 to 0.9 kg per day, with losses falling towards the lower end of the range as the fast extends beyond three weeks.(14,15) Reductions in cardiovascular risk factors are significant, although possible distinct benefits on chemotherapy side effect reduction or improved cancer cytotoxicity may not outweigh risks for those with threatening cachexia, sarcopenia, lymphopenia, or AMPK upregulated cancer subtype.(16) Tumor gene signatures may soon offer insights into these mutations as personalized oncology care continues to evolve. For optimal outcomes, clinicians should carefully monitor patients and modify fasting regimens to individuals needs.
For optimal outcomes, clinicians should carefully monitor patients and modify fasting regimens to individuals needs. I advocate the routine review of our “economy of balance” status checks in our patients as they go through therapy. These individual metrics are basic parameters like, sleep pattern, weight maintenance, muscle mass and function, appetite, energy level, digestive function, activity level, positive emotions and some basic laboratory levels reflecting organ function. Tools like the Oura ring, fit bit, and other wearables, personal inventory measures, and a good health coach and management team can aid in objectifying these measures. The knowledge that these parameters are critical and can empower patients to better understand their needs and dangers to aid them in their path to survive and thrive.
Stay the course, and be your own best doctor,
Charles J. Meakin MD, MHA, MS
Chief Medical Executive Care Oncology
Facebook Page: https://www.facebook.com/CareOncology/
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