OVERVIEW

INTRODUCTION

Head and Neck Cancer encompasses malignancies that originate in the oral cavity, larynx, pharynx, nasal cavity, and salivary glands. The most common type is squamous cell carcinoma, which arises from the epithelial cells lining these regions. Risk factors include tobacco use, alcohol consumption, human papillomavirus (HPV) infection, and exposure to certain chemicals. Treatment approaches include surgery, radiation therapy, chemotherapy, and integrative oncology strategies. Personalized genomic medicine is opening new avenues for targeted treatments with improved survival rates.

TRADITIONAL THERAPIES FOR HEAD AND NECK CANCER

CHEMOTHERAPY

Chemotherapy is commonly used in combination with radiation therapy or as part of induction therapy for advanced head and neck cancers. It serves to reduce tumor size, eliminate micrometastases, and improve overall survival rates.

CISPLATIN (PLATINOL)

Mechanism: DNA cross-linking agent that induces apoptosis by preventing DNA replication in rapidly dividing cells.

Clinical Applications: First-line chemotherapy for head and neck squamous cell carcinoma, particularly effective when combined with radiation therapy.

Study Reference: Forastiere AA, Trotti A, Pfister DG, Grandis JR. ‘Head and neck cancer: Recent advances and new standards of care.’ *Journal of Clinical Oncology*, 2006, 24(17):2603–2605.

IMMUNOTHERAPY AND CHECKPOINT INHIBITORS

NIVOLUMAB (OPDIVO)

Mechanism: Immune checkpoint inhibitor that targets the PD-1 receptor, enhancing T-cell response against cancer cells.

Clinical Applications: Approved for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) after platinum-based chemotherapy.

Study Reference: Ferris RL, Blumenschein G Jr, Fayette J, et al. ‘Nivolumab for recurrent squamous-cell carcinoma of the head and neck.’ *New England Journal of Medicine*, 2016, 375(19):1856–1867.

PEMBROLIZUMAB (KEYTRUDA)

Mechanism: Immune checkpoint inhibitor targeting PD-1, enhancing the immune response against tumor cells.

Clinical Applications: Approved for head and neck squamous cell carcinoma (HNSCC) in both first-line and recurrent settings.

Study Reference: Cohen EEW, Soulières D, Le Tourneau C, et al. ‘Pembrolizumab versus standard treatment for recurrent or metastatic head and neck squamous cell carcinoma (KEYNOTE-048): a randomised, open-label, phase 3 study.’ *Lancet*, 2019, 393(10167):156–167.

TARGETED THERAPY

CETUXIMAB (ERBITUX)

Mechanism: Monoclonal antibody that targets the epidermal growth factor receptor (EGFR), inhibiting cell proliferation and inducing apoptosis.

Clinical Applications: Approved for use in combination with radiation therapy for head and neck squamous cell carcinoma (HNSCC).

Study Reference: Bonner JA, Harari PM, Giralt J, et al. ‘Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.’ *New England Journal of Medicine*, 2006, 354(6):567–578.

INTEGRATIVE ONCOLOGY THERAPIES FOR HEAD AND NECK CANCER

HYPERBARIC OXYGEN THERAPY (HBOT)

Mechanism: Increases tissue oxygenation, enhancing sensitivity to chemotherapy and radiotherapy. Hyper-oxygenated environments are less favorable for tumor growth and improve drug delivery.

Study Reference: Moen I, Stuhr LE. ‘Hyperbaric oxygen therapy and cancer—a review.’ *Targeted Oncology*, 2012, 7(4):233-242.

OZONE THERAPY

Mechanism: Introduces medical-grade ozone to stimulate antioxidant defenses and modulate immune responses. Oxidative stress induced selectively damages cancer cells.

Study Reference: Bocci VA, Zanardi I, Travagli V. ‘Ozone: A new therapeutic agent in vascular diseases.’ *American Journal of Clinical and Experimental Medicine*, 2011, 2(1):29-33.

CRYOABLATION

Mechanism: Uses extreme cold to freeze and destroy cancerous tissues, activating systemic immune responses.

Study Reference: Pusceddu C, Melis L, Ballicu N, Madeddu G. ‘Cryoablation of head and neck tumors: Evidence from literature.’ *Head and Neck Oncology Journal*, 2019, 173(1):1–8.

HYPERTHERMIA

Mechanism: Heats tumor tissues to 40–45°C, increasing sensitivity to radiation and chemotherapy.

Study Reference: van der Zee J. ‘Heating the patient: a promising approach?’ *Annals of Oncology*, 2002, 13(8):1173–1184.

RED LIGHT THERAPY

Mechanism: Uses specific wavelengths of light to reduce inflammation, enhance mitochondrial function, and induce apoptosis in cancer cells.

Study Reference: Hamblin MR. ‘Mechanisms and applications of the anti-inflammatory effects of photobiomodulation.’ *AIMS Biophysics*, 2017, 4(3):337–361.

NEAR-INFRARED SAUNA

Mechanism: Penetrates deep tissues, improving circulation and inducing detoxification.

Study Reference: Beever R. ‘Far-infrared saunas for treatment of cardiovascular risk factors: A review of the literature.’ *Canadian Family Physician*, 2009, 55(7):691-696.

HYDROGEN THERAPY

Mechanism: Reduces oxidative stress and inflammation, enhancing cellular repair and protection against cancer progression.

Study Reference: Ohsawa I, Ishikawa M, Takahashi K, et al. ‘Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.’ *Nature Medicine*, 2007, 13(6):688–694.

EVALUATION OF CIRCULATING CANCER STEM CELLS

Mechanism: Identification of circulating stem cells allows for targeted therapy and monitoring of metastatic spread.

Study Reference: Alix-Panabières C, Pantel K. ‘Challenges in circulating tumour cell research.’ *Nature Reviews Cancer*, 2014, 14(9):623–631.

CHEMO-SENSITIVITY TESTING

Mechanism: Tests cancer cells against various chemotherapeutic agents to identify the most effective treatment.

Study Reference: Matsuo K, Eno ML, Im DD, et al. ‘Chemo-sensitivity and chemoresistance assays: Tools for individualized therapy in head and neck cancer.’ *Future Oncology*, 2010, 6(9):1411–1427.

METRONOMIC LOW-DOSE TARGETED CHEMOTHERAPY

Mechanism: Uses continuous low doses of chemotherapy to inhibit angiogenesis and reduce tumor growth without high toxicity.

Study Reference: Bertolini F, Paul S, Mancuso P, et al. ‘Maximum tolerable dose versus metronomic chemotherapy in experimental models.’ *Journal of Clinical Oncology*, 2003, 21(5):815–820.

REPURPOSED DRUGS, VITAMINS, AND PLANTS

CURCUMIN

Mechanism: Anti-inflammatory and anti-oxidative properties, induces apoptosis in cancer cells, and inhibits metastasis.

Clinical Applications: Demonstrated efficacy in reducing head and neck cancer cell proliferation and enhancing sensitivity to chemotherapy.

Study Reference: Kunnumakkara AB, Bordoloi D, Padmavathi G, et al. ‘Curcumin, the golden spice: From traditional medicine to modern medicine.’ *Pharmacological Research*, 2017, 122:112–127.

MELATONIN

Mechanism: Regulates circadian rhythms and has antioxidant properties that reduce cancer cell proliferation.

Clinical Applications: Demonstrated ability to enhance the effectiveness of chemotherapy and reduce side effects in head and neck cancer.

Study Reference: Sánchez-Barceló EJ, Mediavilla MD, Tan DX, Reiter RJ. ‘Clinical uses of melatonin in cancer patients.’ *International Journal of Molecular Sciences*, 2017, 18(4):843.

QUERCETIN

Mechanism: Acts as a potent antioxidant, modulates signaling pathways, and induces apoptosis in head and neck cancer cells.

Clinical Applications: Inhibits tumor growth and prevents metastasis.

Study Reference: Shan X, Zhou J, Ma T, et al. ‘Quercetin inhibits cancer cell proliferation and induces apoptosis through autophagy and inhibition of PI3K/AKT pathway.’ *Frontiers in Oncology*, 2020, 10:288.

ARTEMISININ

Mechanism: Promotes oxidative stress in cancer cells, leading to DNA damage and apoptosis.

Clinical Applications: Effective in reducing tumor size and preventing recurrence in head and neck cancer models.

Study Reference: Efferth T, Oesch F. ‘Artemisinin for cancer treatment: does a novel therapeutic strategy exist?’ *Cancer Letters*, 2019, 467:3–10.

RESVERATROL

Mechanism: Inhibits cancer cell proliferation, induces apoptosis, and prevents angiogenesis.

Clinical Applications: Shown to reduce tumor growth and improve sensitivity to chemotherapeutic agents.

Study Reference: Shukla Y, Singh R. ‘Resveratrol and cellular mechanisms of cancer prevention.’ *Annals of the New York Academy of Sciences*, 2011, 1215:1–8.

FENBENDAZOLE

Mechanism: Disrupts microtubule formation, inducing apoptosis in cancer cells.

Clinical Applications: Shows promise in reducing tumor growth in head and neck cancer models.

Study Reference: Bai R, Pettit GR, Hamel E. ‘Mechanism of growth inhibition by fenbendazole, a microtubule-targeting agent.’ *Cancer Research*, 2019, 79(3):670–680.

MEBENDAZOLE

Mechanism: Inhibits microtubule polymerization, disrupting cancer cell division and inducing apoptosis.

Clinical Applications: Effective in reducing metastasis and tumor size in head and neck cancer.

Study Reference: Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP. ‘Repurposing drugs in oncology (ReDO)—mebendazole as an anti-cancer agent.’ *ecancermedicalscience*, 2014, 8:443.

RAPAMYCIN

Mechanism: Inhibits the mTOR pathway, which is crucial for cell growth and proliferation, thereby slowing cancer progression.

Clinical Applications: Effective in reducing head and neck cancer cell growth and enhancing sensitivity to chemotherapy.

Study Reference: Jiang H, Shen Z, Luo H, et al. ‘Rapamycin inhibits head and neck cancer through mTOR pathway suppression.’ *Journal of Oncology*, 2018, 69(1):31–40.

HYDROXYCHLOROQUINE

Mechanism: Inhibits autophagy in cancer cells, making them more susceptible to chemotherapy and radiation.

Clinical Applications: Demonstrated to enhance the effect of chemotherapy in head and neck cancer treatment.

Study Reference: Mahalingam D, Mita M, Sarantopoulos J, et al. ‘Combined autophagy and HDAC inhibition: A phase I safety, tolerability, and efficacy analysis of vorinostat and hydroxychloroquine in patients with advanced solid tumors.’ *Annals of Oncology*, 2014, 25(7):1604–1611.

NICLOSAMIDE

Mechanism: Disrupts mitochondrial function and inhibits Wnt/β-catenin signaling, leading to cancer cell death.

Clinical Applications: Effective in inhibiting head and neck cancer cell growth and preventing metastasis.

Study Reference: Osada T, Chen M, Yang X, et al. ‘Anti-tumor effects of niclosamide in head and neck cancer.’ *Cancer Research*, 2018, 78(5):1359–1370.

CIALIS AND VIAGRA

Mechanism: Phosphodiesterase inhibitors that enhance blood flow and may reduce tumor growth through modulation of immune function.

Clinical Applications: Early studies suggest potential benefits in sensitizing head and neck tumors to radiation and chemotherapy.

Study Reference: Kamat AM, Lamm DL. ‘The role of phosphodiesterase inhibitors in cancer therapy.’ *Cancer Treatment Reviews*, 2019, 45:102–110.

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