The Metabolic Approach to Cancer: Terrain Over Tumor

Rethinking the Battlefield

Standard oncology draws its battle maps around the tumor. The tumor’s mutations, its receptor status, its staging — these define the treatment plan. But there is a growing movement within integrative oncology that asks a fundamentally different question: what made the terrain hospitable to cancer in the first place?

Nasha Winters, ND, FABNO, and Jess Higgins Kelley codified this approach in their 2017 book The Metabolic Approach to Cancer. Winters herself is a stage IV ovarian cancer survivor of over 25 years — alive not because of a single miracle therapy, but because she systematically addressed every element of her metabolic terrain. Her framework does not replace conventional oncology. It expands the playing field.

Thomas Seyfried’s research at Boston College provides the scientific foundation. His mitochondrial metabolic theory proposes that cancer originates not from accumulating genetic mutations (the somatic mutation theory) but from chronic damage to mitochondrial respiration. When mitochondria can no longer perform oxidative phosphorylation efficiently, the cell reverts to fermentation — the Warburg effect. The genetic mutations oncologists observe are consequences of this metabolic derangement, not causes.

This is not fringe theory. The evidence supporting metabolic dysfunction in cancer is extensive. But its clinical implications are radical: if the terrain drives the disease, then modifying the terrain can influence its course.

The 10 Terrain Elements

Winters and Kelley identify 10 interconnected terrain elements that collectively determine cancer risk and progression:

1. Epigenetics — Gene expression is modifiable. Diet, toxins, stress, and lifestyle alter methylation, histone modification, and miRNA expression. Cancer is an epigenetic disease as much as a genetic one.

2. Blood Sugar Balance — Hyperglycemia and hyperinsulinemia feed cancer through IGF-1, PI3K/Akt/mTOR activation, and chronic inflammation. Fasting glucose, fasting insulin, HbA1c, and the Glucose-Ketone Index are critical monitoring tools.

3. Toxic Burden — Carcinogens (pesticides, heavy metals, plasticizers, mycotoxins) accumulate in tissue and disrupt mitochondrial function. Reducing exposure and supporting detoxification are terrain fundamentals.

4. Microbiome — The gut microbiome modulates immunity, inflammation, hormone metabolism (estrobolome), and even chemotherapy response. Dysbiosis contributes to cancer terrain.

5. Immune Function — Cancer is a failure of immune surveillance. NK cells, cytotoxic T cells, and dendritic cells must detect and eliminate abnormal cells. Immune modulation — not just stimulation — is the goal.

6. Inflammation — Chronic, low-grade inflammation (NF-kB, COX-2, IL-6, TNF-alpha) promotes every stage of cancer: initiation, promotion, progression, and metastasis.

7. Blood Circulation and Angiogenesis — Tumors require blood supply. Anti-angiogenic strategies (diet, supplements, exercise) limit tumor nourishment.

8. Hormone Balance — Estrogen dominance, testosterone imbalances, cortisol excess, insulin dysregulation — each creates a hormonal milieu that can promote or inhibit cancer growth.

9. Stress and Biorhythms — Chronic stress (sympathetic dominance, elevated catecholamines) and circadian disruption (melatonin suppression) directly promote cancer biology.

10. Mental and Emotional Health — Unresolved trauma, hopelessness, social isolation, and loss of meaning affect neuroendocrine-immune pathways. The psyche is part of the terrain.

Each element is assessed through specific lab testing and clinical evaluation. Each offers actionable interventions. The integrative oncologist addresses all ten simultaneously — like a gardener attending to soil pH, moisture, sunlight, nutrients, and pests rather than focusing on a single weed.

Press-Pulse Therapeutic Strategy

Seyfried proposes a therapeutic model borrowed from evolutionary biology: press-pulse.

Press = chronic metabolic stress applied to the tumor: dietary glucose restriction (ketogenic diet), caloric restriction, or fasting-mimicking diets. These create a sustained metabolic environment hostile to cancer cells that depend on glucose and glutamine fermentation.

Pulse = acute metabolic interventions applied intermittently: hyperbaric oxygen therapy, 2-deoxyglucose (2-DG, a glucose analog that blocks glycolysis), dichloroacetate (DCA, which reactivates mitochondrial pyruvate dehydrogenase), and targeted pro-oxidant therapies like high-dose IV vitamin C.

The logic is elegant. Normal cells with functional mitochondria can adapt to ketones and low glucose — they are metabolically flexible. Cancer cells with damaged mitochondria cannot — they are metabolically rigid. The press-pulse strategy exploits this rigidity.

The Glucose-Ketone Index (GKI)

The GKI is a simple ratio that quantifies metabolic stress on cancer:

GKI = Blood Glucose (mmol/L) / Blood Ketones (mmol/L)

• GKI > 9: Standard high-carb diet (cancer-permissive)
• GKI 3-9: Mild ketosis (health maintenance)
• GKI 1-3: Therapeutic ketosis (anti-cancer range)
• GKI < 1: Deep therapeutic ketosis (maximum metabolic stress on tumor)

For cancer patients, the target GKI of 1.0-2.0 represents significant glucose restriction combined with robust ketone production. This requires strict dietary adherence and monitoring with a dual glucose-ketone meter.

Ketogenic Diet in Cancer

The Mechanism

Cancer cells upregulate glucose transporters (GLUT1) and glycolytic enzymes. They ferment glucose to lactate even in the presence of oxygen (the Warburg effect). Most cancer cells have impaired or absent ability to metabolize ketone bodies because their mitochondria are dysfunctional — the very organelles needed to oxidize ketones.

Normal cells, by contrast, readily shift from glucose to ketone metabolism. During ketosis, normal cells thrive while cancer cells are metabolically starved.

The Evidence

The evidence base is growing but not yet definitive for clinical outcomes:

• Klement’s 2017 systematic review of preclinical and clinical studies found consistent anti-tumor effects of ketogenic diets, with improved quality of life and no adverse effects on nutritional status in most trials.
• Tan-Shalaby’s 2016 pilot study in advanced cancer patients showed feasibility, safety, and stable disease or partial response in some participants.
• Fine’s 2012 pilot study in advanced cancer patients showed a correlation between degree of ketosis and tumor regression or stabilization.

Implementation

The cancer ketogenic diet is not a casual dietary choice. It requires:

• Macros: 70-80% fat, 15-20% protein (moderate — excess protein converts to glucose via gluconeogenesis), 5-10% net carbs (20-30g/day)
• Fat sources: Olive oil, coconut oil, avocado, nuts, seeds, fatty fish, MCT oil
• Monitoring: Daily GKI measurement, weekly labs initially
• Medical supervision: Essential — especially for patients on medications (insulin, oral hypoglycemics, anti-seizure drugs)
• Contraindications: Cachexia, severe weight loss, fat metabolism disorders, pyruvate carboxylase deficiency

Hyperbaric Oxygen + Ketosis

Poff’s 2013 animal study at the University of South Florida demonstrated that the combination of ketogenic diet plus hyperbaric oxygen therapy (HBOT) produced synergistic anti-tumor effects — decreased tumor growth rate and increased survival in mice with metastatic cancer — greater than either intervention alone.

The mechanism: ketosis creates metabolic stress on the tumor, while hyperbaric oxygen (1.5-2.5 ATA, 60-90 minutes) saturates tissue with oxygen, increasing oxidative stress on cancer cells that have impaired antioxidant defenses. Normal cells handle the increased oxygen; cancer cells with dysfunctional mitochondria cannot.

Clinical application: HBOT is available in many cities, typically 40-60 sessions at 1.5-2.0 ATA. Combined with ketogenic diet and standard treatment, it represents a promising adjunctive approach. Large RCTs are still needed.

Repurposed Drugs — Old Molecules, New Targets

A growing body of research identifies existing, inexpensive drugs with anti-cancer properties that work through metabolic pathways:

Metformin

The world’s most prescribed diabetes drug also inhibits mTOR (via AMPK activation), reduces insulin and IGF-1, activates tumor suppressor pathways, and may directly inhibit mitochondrial Complex I in cancer cells. Decensi’s 2010 meta-analysis showed a 31% reduction in cancer incidence and 34% reduction in cancer mortality in diabetic patients taking metformin. Multiple oncology trials are now testing metformin as adjunct cancer therapy. Dose: 500-2,000 mg/day.

Aspirin

Rothwell’s 2011 landmark analysis of RCTs demonstrated that daily aspirin use (75-325 mg) reduced colorectal cancer incidence by approximately 24% and mortality by 35% with long-term use. Aspirin inhibits COX-2, reduces prostaglandin-mediated inflammation, and may inhibit platelet-cancer cell interaction that promotes metastasis.

Statins

Cholesterol is a critical component of cancer cell membranes and lipid raft signaling. Statins (HMG-CoA reductase inhibitors) may disrupt cancer cell membrane integrity and prenylation of oncogenic Ras proteins. Epidemiological data suggests reduced cancer mortality in statin users.

Doxycycline

This common antibiotic inhibits mitochondrial ribosomes (because mitochondria evolved from bacteria). Lamb’s 2015 research showed doxycycline inhibited cancer stem cell propagation. Dose: 100-200 mg/day.

Mebendazole

An anti-parasitic drug that inhibits tubulin polymerization — the same mechanism as vincristine/vinblastine chemotherapy, but with minimal side effects. Case reports and preclinical data show activity against multiple cancer types. Dose: 100-200 mg/day.

These repurposed drugs are used off-label and should only be prescribed by physicians within a coordinated care-of-cancer framework.

IV Vitamin C — Pharmacologic Ascorbate

At oral doses, vitamin C is an antioxidant. At IV pharmacologic doses (25-100g), it behaves as a pro-oxidant — generating hydrogen peroxide (H2O2) in the extracellular space. Normal cells neutralize H2O2 with catalase. Many cancer cells have reduced catalase activity and are selectively damaged.

The legacy traces to Linus Pauling and Ewan Cameron’s work in the 1970s-80s. Their research was dismissed after Mayo Clinic oral vitamin C trials showed no benefit — but they had used IV, not oral administration. The pharmacokinetics are fundamentally different.

Modern research has revived interest:

• Iowa studies (Chen/Cullen lab) demonstrated pharmacologic ascorbate’s selective cytotoxicity to cancer cells while protecting normal cells
• NCCN now lists high-dose IV vitamin C as a complementary approach worth discussing with patients
• The Riordan Protocol (25-100g IV, 2-3 times/week) is used in integrative oncology clinics worldwide

Key considerations: screen for G6PD deficiency (hemolysis risk), monitor renal function (oxalate nephropathy), avoid within 24-48 hours of certain chemotherapy agents, ensure proper IV administration by trained staff.

Mistletoe (Viscum album)

Mistletoe extract is the most studied complementary cancer therapy in Europe — part of anthroposophic medicine tradition and mainstream integrative oncology in Germany, Switzerland, and Austria.

Mistletoe lectins and viscotoxins are cytotoxic to cancer cells, stimulate immune function (increased NK cells, T cells, dendritic cells), and improve quality of life. Ostermann’s 2020 meta-analysis of 26 RCTs showed significant improvement in quality of life across cancer types, with some studies suggesting survival benefit.

Administration: subcutaneous injection, typically 3 times/week, with doses titrated upward. Brands include Iscador, Helixor, and Abnobaviscum. Must be prescribed and monitored by trained practitioners. Common side effects: local injection site reaction (desired — indicates immune activation), mild fever.

Integration — The Non-Negotiable Principle

Everything in this metabolic approach must be held within one unbreakable frame: never replace standard of care.

The metabolic approach is additive. It addresses the terrain that conventional treatments do not target. Ketogenic diet does not replace chemotherapy. Hyperbaric oxygen does not replace surgery. IV vitamin C does not replace immunotherapy. Repurposed drugs do not replace targeted therapy.

Patients who abandon proven treatments in favor of metabolic therapies alone have worse outcomes. This is documented. The ethical integrative oncologist holds space for both the metabolic terrain and the evidence-based oncologic protocol.

Documentation is essential. Every supplement, every dietary intervention, every off-label drug must be recorded in the medical chart. The oncologist must know. The naturopathic oncologist must know. The pharmacist must check interactions. This is a team sport.

The metabolic approach to cancer gives patients something conventional oncology often does not: a framework for understanding why cancer developed and what they can do about the conditions that enabled it. It transforms the patient from a passive recipient of treatment into an active participant in reshaping their terrain.

The tumor is the symptom. The terrain is the story. If you could read all ten chapters of your metabolic terrain, which chapter would demand your attention first?